Substituted Heteroaryls

ABSTRACT

The present invention provides Formula (1A) compounds 
     
       
         
         
             
             
         
       
     
     that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase. X, Y, Z, R 1 , R 2 , R 3 , and R 4  areas described herein.

This application is a continuation of U.S. application Ser. No.13/116,398 filed May 26, 2011, which is a divisional of U.S. applicationSer. No. 12/556,086 filed Sep. 09, 2009 now U.S. Pat. No. 7,977,367issued Jul. 12, 2011, which claims the benefit of priority from U.S.Provisional Application No. 61/232,578, filed Aug. 10, 2009 and U.S.Provisional Application No. 61/096,056 filed Sep. 11, 2008, each ofwhich are herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to substituted heteroaryls and the usesthereof as glucokinase activators.

BACKGROUND

Diabetes is a major public health concern because of its increasingprevalence and associated health risks. The disease is characterized bymetabolic defects in the production and utilization of carbohydrateswhich result in the failure to maintain appropriate blood glucoselevels. Two major forms of diabetes are recognized. Type I diabetes, orinsulin-dependent diabetes mellitus (IDDM), is the result of an absolutedeficiency of insulin. Type II diabetes, or non-insulin dependentdiabetes mellitus (NIDDM), often occurs with normal, or even elevatedlevels of insulin and appears to be the result of the inability oftissues and cells to respond appropriately to insulin. Aggressivecontrol of NIDDM with medication is essential; otherwise it can progressinto IDDM.

As blood glucose increases, it is transported into pancreatic beta cellsvia a glucose transporter. Intracellular mammalian glucokinase (GK)senses the rise in glucose and activates cellular glycolysis, i.e. theconversion of glucose to glucose-6-phosphate, and subsequent insulinrelease. Glucokinase is found principally in pancreatic β-cells andliver parenchymal cells. Because transfer of glucose from the blood intomuscle and fatty tissue is insulin dependent, diabetics lack the abilityto utilize glucose adequately which leads to undesired accumulation ofblood glucose (hyperglycemia). Chronic hyperglycemia leads to decreasesin insulin secretion and contributes to increased insulin resistance.Glucokinase also acts as a sensor in hepatic parenchymal cells whichinduces glycogen synthesis, thus preventing the release of glucose intothe blood. The GK processes are thus critical for the maintenance ofwhole body glucose homeostasis.

It is expected that an agent that activates cellular GK will facilitateglucose-dependent secretion from pancreatic beta cells, correctpostprandial hyperglycemia, increase hepatic glucose utilization andpotentially inhibit hepatic glucose release. Consequently, a GKactivator may provide therapeutic treatment for NIDDM and associatedcomplications, inter alia, hyperglycemia, dyslipidemia, insulinresistance syndrome, hyperinsulinemia, hypertension, and obesity.

Several drugs in five major categories, each acting by differentmechanisms, are available for treating hyperglycemia and subsequently,NIDDM (Moller, D. E., “New drug targets for Type II diabetes and themetabolic syndrome” Nature 414; 821-827, (2001)): (A) Insulinsecretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride,glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhancesecretion of insulin by acting on the pancreatic beta-cells. While thistherapy can decrease blood glucose level, it has limited efficacy andtolerability, causes weight gain and often induces hypoglycemia. (B)Biguanides (e.g., metformin) are thought to act primarily by decreasinghepatic glucose production. Biguanides often cause gastrointestinaldisturbances and lactic acidosis, further limiting their use. (C)Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinalglucose absorption. These agents often cause gastrointestinaldisturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone)act on a specific receptor (peroxisome proliferator-activatedreceptor-gamma) in the liver, muscle and fat tissues. They regulatelipid metabolism subsequently enhancing the response of these tissues tothe actions of insulin. Frequent use of these drugs may lead to weightgain and may induce edema and anemia. (E) Insulin is used in more severecases, either alone or in combination with the above agents.

Ideally, an effective new treatment for NIDDM would meet the followingcriteria: (a) it would not have significant side effects includinginduction of hypoglycemia; (b) it would not cause weight gain; (c) itwould at least partially replace insulin by acting via mechanism(s) thatare independent from the actions of insulin; (d) it would desirably bemetabolically stable to allow less frequent usage; and (e) it would beusable in combination with tolerable amounts of any of the categories ofdrugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated inmediating GK and may play a significant role in the treatment of NIDDM.For example, U.S. Patent publication No. 2006/0058353 and PCTpublication Nos. WO2007/043638, WO2007/043638, and WO2007/117995 recitecertain heterocyclic derivatives with utility for the treatment ofdiabetes. Although investigations are on-going, there still exists aneed for a more effective and safe therapeutic treatment for diabetes,particularly NIDDM.

SUMMARY OF THE INVENTION

The present invention provides Formula (1A) compounds that act asglucokinase modulators, in particular, glucokinase activators;therefore, may be used in the treatment of diseases mediated by suchactivation (e.g., diseases related to Type 2 diabetes, anddiabetes-related and obesity-related co-morbidities).

wherein

X, Y, and Z are each independently C(R) or N, where R is H, halo,halo-substituted (C₁-C₃)alkyl, (C₁-C₆)alkyl, or (C₁-C₆)alkoxy, and X, Y,and Z are not all N;

R¹ is H, (C₁-C₆)alkyl, halo-substituted (C₁-C₃)alkyl, —S(O)₂(R^(1a)), orC(O)R^(1a), where R^(1a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylamino, or di-(C₁-C₃)alkylamino;

R² is (C₃-C₆)cycloalkyl or 5- to 6-membered heterocycle containing oneN, O, or S heteroatom, where said cycloalkyl and said heterocycle areoptionally substituted with one to two substituents each independentlyhalo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, or cyano;

R³ is H or (C₁-C₆)alkyl; and

R⁴ is quinolinyl, thiazolo[5,4-b]pyridinyl or 5- to 6-memberedheteroaryl containing one to two N heteroatoms and optionally one O or Sheteroatom, where said heteroaryl, quinolinyl andthiazolo[5,4-b]pyridinyl are optionally substituted with one to twoR^(4a), where each R^(4a) is independently (C₁-C₆)alkyl optionallysubstituted with one to three hydroxy, —CF₃, cyano, (C₁-C₆)alkoxy, halo,amino, (C₁-C₃)alkylamino, di-(C₁-C₃)alkylamino, —CO₂R^(4b),—(C₁-C₆)alkylCO₂R^(4b), —C(O)N(R^(4b))₂, —P(O)(OR_(4b))₂,—(C₁-C₆)alkylP(O)(OR_(4b))₂, —P(O)(OR^(4b))(C₁-C₃alkyl),(C₁-C₃)alkylsufonyl, —SO₃H, —NHC(O)R^(4c) or aryl(C₁-C₆)alkyl, where thearyl of said arylalkyl is optionally substituted with (C₁-C₆)alkyl,—CF₃, cyano, (C₁-C₆)alkoxy, halo, amino, (C₁-C₃)alkylamino, ordi-(C₁-C₃)alkylamino;

R^(4b) at each occurrence is independently hydrogen, (C₁-C₆)alkyl orbenzyl; and R^(4c) at each occurrence is independently CO₂H or(C₁-C₆)alkyl optionally substituted with one to three hydroxy; or apharmaceutically acceptable salt thereof.

R¹ is preferably H, methyl, ethyl, —CF₃, —S(O)₂(R^(1a)), or C(O)R^(1a),where R^(1a) is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,(C₁-C₃)alkylamino, or di-(C₁-C₃)alkylamino. More preferred, R¹ is H,methyl, ethyl, —CF₃, —S(O)₂CH₃, —S(O)₂CH₂CH₃, —S(O)₂CH(CH₃)₂,—S(O)₂cyclopropyl, —S(O)₂cyclobutyl, —C(O)NHCH₃, —C(O)NHCH₂CH₃, or—C(O)N(CH₃)₂. Most preferred, R¹ is H, methyl, —CF₃, —S(O)₂CH₃,—S(O)₂CH₂CH₃, —S(O)₂CH(CH₃)₂, —S(O)₂cyclobutyl, or —C(O)N(CH₃)₂.

R² is preferably (C₃-C₆)cycloalkyl or 5- to 6-membered heterocyclecontaining one N, O, or S heteroatom, where said cycloalkyl and saidheterocycle are optionally substituted with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —CF₃, or cyano. More preferred, R² is cyclobutyl,cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydropyranyl, eachoptionally substituted with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, orcyano. Most preferred, R² is cyclopentyl or tetrahydropyranyl.

R³ is preferably H, methyl, or ethyl. Most preferred, R³ is H.

R⁴ is preferably pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,or quinolinyl, each optionally substituted with one to two R^(4a), whereR^(4a) is as described above. More preferred, R⁴ is pyrazolyl,isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, eachoptionally substituted with one to two R^(4a), where R^(4a) is asdescribed above. Most preferred, R⁴ is pyrazolyl, isoxazolyl, pyridinyl,pyrazinyl, pyrimidinyl, quinolinyl, or a Formula of (a), (b), (c), (d),or (e),

where R^(4a) is methyl, ethyl, —CF₃, —CO₂H, —CH₂CO₂H, —P(O)(OH)₂,—CH₂P(O)(OH)₂, —SO₃H or benzyl.

A preferred compound of the present invention is a compound of Formula(1B)

where R¹, R², and R⁴ are as described above.

Preferred compounds of Formula (1B) include(S)-30cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl-1H-pyrazol-1-yl)-N-(pyrazin-2-yl)propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl-1H-pyrazol-1-yl)-N-(pyrimidin-4-yl)-propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(pyrimidin-2-yl)-propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5methylpyrazin-2yl)-propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1yl)-N-(1-methyl-1H-pyrazol-3yl)-propanamide;(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-(methylsulfonyl-1H-pyrazol-1-yl)-propanamide;(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)-propanamide;(S)-3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)propanamide;(S)-3-cyclopentyl-N-(1-ethyl-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)-propanamide;(S)—N-(1-benzyl-1H-pyrazol-3-yl)-3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)-propanamide;(S)-3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)-N-(pyrimidin-4-yl)propanamide;(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)-propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(isoxazol-3-yl)-propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(pyridin-2-yl)propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(quinolin-2-yl)-propanamide;(S)-3-cyclopentyl-N-(1-ethyl-1H-pyrazol-3-yl)-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-propanamide;(S)—N-(1-benzyl-1H-pyrazol-3-yl)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-propanamide;(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-pyrazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-propanamide;(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methylpyridin-2-yl)-propanamide;(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methylpyrazin-2-yl)-propanamide;(S)-benzyl6-(3-cylclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanamido)nicotinate;and(S)-6-(3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanamido)nicotinicacid; or a pharmaceutically acceptable salt thereof.

Another preferred compound of the present invention is a compound ofFormula (1C)

where R¹, R², and R⁴ are as described above.

Preferred compounds of Formula (1)include(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)propanamide;(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)-N-(5-methylpyrazin-2-yl)propanamide;(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)propanamide;(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide;(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)-N-(5-methylpyrazin-2-yl)propanamide;(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamide;(S)-benzyl6-(3-cyclopentyl-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinate;(S)-6-(3-cyclopentyl-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinicacid;(S)-6-(3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinicacid;(S)-6-(3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinicacid;(S)-6-(2-(4-(cyclobutylsulfonyl)-1H-imidazol-1-yl)-3-cyclopentylpropanamido)nicotinicacid;6-[(S)-3-cyclopentyl-2-(4-dimethylsulfamoyl-imidazol-1-yl)-propionylamino]nicotinicacid;(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)-methyl6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate;(S)-benzyl6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate;(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinicacid;(S)-3-cyclopentyl-N-(2-ethyl-2H-[1,2,3]triazol-4-yl)-2-(4-trifluoromethyl-1H-imidazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(5-((S)-1,2-dihydroxyethyppyrazin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)-3-cyclopentyl-N-[5-(methylsulfonyl)pyridin-2-yl]-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propanamide;6-[(S)-3-cyclopentyl-2-(4-trifluoromethyl-1H-imidazol-1-yl)-propionylamino]nicotinamide;(S)-benzyl5-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyrazine-2-carboxylate;(S)-5-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyrazine-2-carboxylicacid; (S)-ethyl2-(3-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)-1H-pyrazol-1-yl)acetate;(S)-3-cyclopentyl-N-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)-2-(3-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)-1H-pyrazol-1-yl)aceticacid;(S)-diethyl(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)methylphosphonate;(S)-diethyl6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-ylphosphonate;(S)-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)methylphosphonicacid;(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridine-3-sulfonicacid;(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-ylphosphonicacid;6-((S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl(methyl)phosphinicacid;(S)-2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)aceticacid;(S)-2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)-2-methylpropanoicacid;(S)-2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-ylamino)-2-oxoaceticacid; and(S)-3-Cyclopentyl-N-[5-(2-hydroxy-2-methyl-propionylamino)-pyridin-2-yl]-2-(4-trifluoromethyl-imidazol-1-yl)-propionamide;(S)—N-(5-methylpyrazin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)—N-(5-methylpyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)—N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)-3-(tetrahydro-2H-pyran-4-yl)-N-(thiazolo[5,4-b]pyridin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)—N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(2S)—N-(5-methylpyridin-2-yl)-3-(tetrahydrofuran-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)—N-(5-methylpyridin-2-yl)-3-(1H-pyrazol-1-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;and(S)-6-(3-cyclohexyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinicacid; or a pharmaceutically acceptable salt thereof.

More preferred compounds of Formula (1C) include(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)-propanamide;(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)-propanamide;(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)-propanamide;(S)—N-(5-methylpyrazin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)—N-(5-methylpyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide;(S)-6-(3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinicacid;(S)-6-(2-(4-(cyclobutylsulfonyl)-1H-imidazol-1-yl)-3-cyclopentylpropanamido)nicotinicacid;(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinicacid;(S)-2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)aceticacid; and(S)-6-(3-cyclohexyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinicacid; or a pharmaceutically acceptable salt thereof.

Another preferred compound of the present invention is a compound ofFormula (1D)

where R¹, R², and R⁴ are as described above.

Preferred compounds of Formula (1D) include(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide;and(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide;or a pharmaceutically acceptable salt thereof.

Another preferred compound of the present invention is a compound ofFormula (1E)

where the R¹, R², and R⁴ are as described above.

Preferred compounds of Formula (1E) include(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(3-(methylsulfonyl)-1H-1,2,4-triazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)-1H-1,2,4-triazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(3-(methylsulfonyl)-1H-1,2,4-triazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(pyrazin-2-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamide;(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamide;(S)-benzyl6-(3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamido)nicotinate;(S)-ethyl2-(3-(3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamido)-1H-pyrazol-1-yl)acetate;(S)-6-(3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamido)nicotinicacid; and(S)-2-(3-(3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamido)-1H-pyrazol-1-yl)aceticacid; or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is a pharmaceutical compositionthat comprises (1) a compound of the present invention, or apharmaceutically acceptable salt thereof; and (2) a pharmaceuticallyacceptable excipient, diluent, or carrier. Preferably, the compositioncomprises a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient, diluent, or carrier.

The composition may comprise at least one additional pharmaceuticalagent, or a pharmaceutically acceptable salt thereof. Preferredadditional pharmaceutical agents include anti-diabetic, anti-obesity,anti-hypertension, anti-hyperglycemic, and lipid lowering agents, asdescribed herein. More preferred, are anti-diabetic and anti-obesityagents, as described herein.

In yet another aspect of the present invention is a method for treatinga disease, condition, or disorder mediated by the glucokinase enzyme, inparticular, activation of said enzyme, in a mammal that includes thestep of administering to a mammal, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutical composition thereof.

Diseases, disorders, or conditions mediated by glucokinase activatorsinclude Type II diabetes, hyperglycemia, metabolic syndrome, impairedglucose tolerance, glucosuria, cataracts, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension,hyperinsulinemia, and insulin resistance syndrome. Preferred diseases,disorders, or conditions include Type II diabetes, hyperglycemia,impaired glucose tolerance, obesity, and insulin resistance syndrome.More preferred are Type II diabetes, hyperglycemia, and obesity. Mostpreferred is Type II diabetes.

In yet another aspect of the present invention is a method of reducingthe level of blood glucose in a mammal, preferably a human, whichincludes the step of administering to a mammal in need of such treatmenta therapeutically effective amount of a compound of the presentinvention, or a pharmaceutical composition thereof.

Compounds of the present invention may be administered in combinationwith other pharmaceutical agents (in particular, anti-obesity andanti-diabetic agents described herein). The combination therapy may beadministered as (1) a single pharmaceutical composition which comprisesa compound of the present invention, at least one additionalpharmaceutical agent described herein and a pharmaceutically acceptableexcipient, diluent, or carrier; or (2) two separate pharmaceuticalcompositions comprising (i) a first composition comprising a compound ofthe present invention and a pharmaceutically acceptable excipient,diluent, or carrier, and (ii) a second composition comprising at leastone additional pharmaceutical agent described herein and apharmaceutically acceptable excipient, diluent, or carrier. Thepharmaceutical compositions may be administered simultaneously orsequentially and in any order.

DEFINITIONS

For purposes of the present invention, as described and claimed herein,the following terms and phrases are defined as follows:

“Activate(s)” or “activator”, or “activation”, as used herein, unlessotherwise indicated, refers to the ability of the compounds of thepresent invention to indirectly or directly bind to the GK enzyme in amammal as a ligand thereby partially or wholly activating said enzyme.

“Additional pharmaceutical agent(s)” as used herein, unless otherwiseindicated, refers to other pharmaceutical compounds or products thatprovide a therapeutically effective amount of said agents that areuseful for the treatment of a disease, condition, or disorder, asdescribed herein.

“Alkoxy”, as used herein, unless otherwise indicated, refers to anoxygen moiety having a further alkyl substituent. The alkyl portion(i.e., alkyl moiety) of an alkoxy group has the same definition asbelow. “Alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon alkane radicals of the general formulaC_(n)H_(2n+1). The alkane radical may be straight or branched and may beunsubstituted or substituted. For example, the term “(C₁-C₆) alkyl”refers to a monovalent, straight or branched aliphatic group containing1 to 6 carbon atoms. Non-exclusive examples of (C₁-C₆) alkyl groupsinclude, but are not limited to methyl, ethyl, propyl, isopropyl,sec-butyl, t-butyl, n-propyl, n-butyl, i-butyl, s-butyl, n-pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl,3,3-dimethylpropyl, 2-methylpentyl, hexyl, and the like. Alkylrepresented along with another term (e.g., alkylamino (e.g., CH₃NH—),aminoalkyl (e.g., NH₂CH₂—), di-alkylamino (e.g., (CH₃)₂N—), arylalkyl(e.g., benzyl), and the like) where said alkyl moiety has the samemeaning as above and may be attached to the chemical moiety by any oneof the carbon atoms of the aliphatic chain.

“Aryl”, as used herein, unless otherwise indicated, refers to amonocyclic, bicyclic, or fused ring system wherein each ring isaromatic. A typical aryl group (e.g. phenyl, naphthyl) is a 6- to10-membered carbocyclic ring or ring system. The aryl group may beattached to the chemical moiety by any one of the carbon atoms withinthe ring system. Aryl rings are optionally substituted with one to threesubstituents and may be fused to a heteroaryl to form an aromaticheteroaryl ring system.

“Compounds of the present invention”, as used herein, unless otherwiseindicated, refers to compounds of Formula (1A), pharmaceuticallyacceptable salts of the compounds, as well as, all stereoisomers (e.g.,enantiomers), tautomers and isotopically labeled compounds, and aretherefore considered equivalents of the compounds of the presentinvention. Solvates and hydrates of the Formula (1A) compounds, or apharmaceutically acceptable salt thereof, are considered compositions.

“Cycloalkyl”, as used herein, unless otherwise indicated, includes fullysaturated or partially saturated carbocyclic alkyl moieties, whereinalkyl is as defined above. Preferred cycloalkyls are 3- to 6-memberedmonocyclic rings including cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. The cycloalkyl group may be attached to the chemical moietyby any one of the carbon atoms within the carbocyclic ring. Cycloalkylgroups are optionally substituted with one to three substituents. The 5-to 6-membered cycloalkyls may be fused with a heteroaryl to form aheteroaryl ring system.

“Diabetes”, as used herein, unless otherwise indicated, refers tometabolic defects in the production and utilization of carbohydrates,particularly glucose, which result in the failure of glucosehomeostasis. Preferred forms of diabetes include Type I diabetes, orinsulin-dependent diabetes mellitus (IDDM) which results from theabsolute deficiency of insulin and Type II diabetes, or non-insulindependent diabetes mellitus (NIDDM), which often occurs with normal, oreven elevated levels of insulin and appears to be the result of theinability of mammalian cells and tissues to respond appropriately toinsulin. Most preferred is NIDDM.

“Diabetes-related disorder”, as used herein, unless otherwise indicated,refers to metabolic syndrome (Syndrome X, or elevated blood glucose,hypertension, obesity, dyslipidemia), hyperglycemia, hyperinsulinemia,impaired glucose tolerance, impaired fasting glucose, insulinresistance, obesity, atherosclerotic disease, cardiovascular disease,cerebrovascular disease, peripheral vessel disease, lupus, polycysticovary syndrome, carcinogenesis, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, diabetic macular edema, andhyperplasia.

“Halo-substituted alkyl”, unless otherwise indicated, refers to an alkylgroup substituted with one or more halogen atoms (e.g., chloromethyl,dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,perfluoroethyl, and the like. When substituted, the alkane radicals arepreferably substituted with 1 to 3 fluoro substituents.

“Heteroaryl”, as used herein, unless otherwise indicated, refers to anaromatic monocyclic or fused ring containing one or more heteroatomseach independently selected from N, O, or S, preferably from one tothree heteroatoms. Non-exclusive examples of monocyclic rings includepyrolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, thiazolyl,oxadiazolyl, pyridinyl, tetrazolyl, pyridazinyl, pyrimidinyl, and thelike. Non-exclusive examples of fused rings include: quinolinyl,cinnolinyl, benzofuranyl, benzothiazolyl, indolyl, iso-indolyl,indazolyl, and the like. The heteroaryl group may be attached to thechemical moiety by any one of the carbon atoms or heteroatoms (e.g., N,O, and S) within the ring. Heteroaryls are optionally substituted withone to three substituents.

“Heterocycle”, as used herein, unless otherwise indicated, refers tonon-aromatic rings containing one or more heteroatoms each independentlyselected from N, O, or S, preferably from one to three heteroatoms, thatare either partially saturated or fully saturated and may exist as amonocyclic or fused ring. Non-exclusive examples of monocyclicheterocycles include: tetrahydrofuranyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl,azathianyl, and the like. Non-exclusive examples of fused heterocyclesinclude: 6,7-dihydro-5H-[1]pyridinyl, thiazolo[5,4-b]pyridinyl,2,3-dihydro-1H-pyrrolo[2,3-c]pyridinyl, and the like. The heterocyclicgroup may be attached to the chemical moiety by any one of the carbonatoms or heteroatoms (e.g. N, O, and S) within the ring system.Heterocycles are optionally substituted with one to three substituents.

“Mammal”, or “mammalian” as used herein, unless otherwise indicated,refers to an individual animal that is a member of the taxonomic classMammalia. Non-exclusive examples of mammals include humans, dogs, cats,horses, and cattle, preferably human.

“Mediate(s)” or “mediated”, as used herein, unless otherwise indicated,refers to the activation (e.g., partial or full) of the glucokinaseenzyme by enhancing glucose binding, alleviating the inhibition ofglucokinase regulatory protein, a key regulator of glucokinase activityin the liver, and/or to increase the catalytic rate of the glucokinaseenzyme (e.g., change Vmax).

“Obesity” and “obese”, as used herein, unless otherwise indicated,refers generally to individuals who are at least about 20-30% over theaverage weight for his/her age, sex and height. Technically, obese isdefined, for males and females, as individuals whose body mass index isgreater than 27.8 kg/m², and 27.3 kg/m², respectively. Those of skill inthe art readily recognize that the invention method is not limited tothose who fall within the above criteria. Indeed, the method of theinvention can also be advantageously practiced by individuals who falloutside of these traditional criteria, for example, by those who may beprone to obesity.

“Pharmaceutically acceptable” as used herein, unless otherwiseindicated, indicates that the substance or composition must becompatible chemically and/or toxicologically, with the other ingredientscomprising a formulation, composition, and/or the mammal being treatedtherewith.

“Reducing the level of blood glucose”, or “lower blood glucose” as usedherein, unless otherwise indicated, refers to an amount of the compoundof the present invention sufficient to provide circulatingconcentrations of the compound high enough to accomplish the desiredeffect of lowering blood glucose levels in a mammal.

“Therapeutically effective amount”, as used herein, unless otherwiseindicated, refers to an amount of the compounds of the present inventionthat (i) treats or prevents the particular disease, condition, ordisorder, (ii) attenuates, ameliorates, or eliminates one or moresymptoms of the particular disease, condition, or disorder, or (iii)prevents or delays the onset of one or more symptoms of the particulardisease, condition, or disorder described herein.

“Treatment”, “treating”, and the like, as used herein, unless otherwiseindicated, refers to reversing, alleviating, or inhibiting the progressof the disorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. As used herein, these terms alsoencompass, depending on the condition of the mammal, preferably a human,preventing the onset of a disorder or condition, or of symptomsassociated with a disorder or condition, including reducing the severityof a disorder or condition or symptoms associated therewith prior toaffliction with said disorder or condition. Thus, treatment can refer toadministration of the compounds of the present invention to a mammalthat is not at the time of administration afflicted with the disorder orcondition. Treating also encompasses preventing the recurrence of adisorder or condition or of symptoms associated therewith.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides Formula (1A) compounds, orpharmaceutically acceptable salts thereof, compositions andpharmaceutical compositions that are useful in the treatment ofdiseases, disorders, or conditions mediated by glucokinase activation,in particular, compounds that activate glucokinase in a mammal,preferably a human.

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, “Reagents for Organic Synthesis”, 1; 19, Wiley, New York (1967,1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements (also available via theBeilstein online database)).

For illustrative purposes, the reaction schemes depicted belowdemonstrate potential routes for synthesizing compounds of the presentinvention, and key intermediates. For a more detailed description of theindividual reaction steps, see the Examples section below. Those skilledin the art will appreciate that other suitable starting materials,reagents, and synthetic routes may be used to synthesize the compoundsof the present invention and a variety of derivatives thereof. Further,many of the compounds prepared by the methods described below can befurther modified in light of this disclosure using conventionalchemistry well known to those skilled in the art.

Compounds of the present invention described herein contain at least oneasymmetric or chiral center; and therefore, exist in differentstereoisomeric forms. The R and S configurations are based uponknowledge of known chiral inversion/retention chemistry by those skilledin the art. For example, the chirality of an intermediate undergoes aninversion when a neucleophile attacks from the opposite side of theleaving group, the product could be designated as R or S depending onthe priorities of the groups attached to the stereocenter(Stereochemistry of Organic Compounds, by Ernest L. Eliel, Samuel H.Wilen, John Wiley and Sons, Inc.(1994)). Whereas, if a nucleophileattaches to the same side as the leaving group the chirality ofintermediate is retained. In most of the examples, there is an inversionof the configuration where a compound with R configuration is convertedto compound with a S configuration as the priorities of the all the foursubstituents at the stereocenter is retained. It is further noted thatthe intermediates can also be racemic (50:50 mixture of stereoisomer)thereby producing racemic products. A chiral separation method can beused to separate these enantiomers to provide the specific R or Sisomers. It is further noted that the intermediates can also be racemicthereby producing racemic products. A more detailed description oftechniques that can be used to resolve stereoisomers of compounds fromtheir racemic mixture can be found in Jean Jacques Andre Collet, SamuelH. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons,Inc. (1981). In addition, the present invention embraces all geometricand positional isomers. For example, if a compound of the presentinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesfrom undesired reactions with a protecting or blocking group. The term“protecting group” or “Pg” refers to a substituent that is commonlyemployed to block or protect a particular functionality while reactingother functional groups on the compound. For example, an amineprotecting group “Pg¹” or a carboxyl protecting group “Pg²” is asubstituent attached to an amine or carboxyl group that blocks orprotects the amine or carboxyl functionality, respectively, of thecompound. Suitable amine protecting groups include:1-tert-butyloxycarbonyl (Boc), acyl groups including: formyl, acetyl,chloroacetyl, trichloro-acetyl, o-nitrophenylacetyl,o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl,isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate,aminocaproyl, benzoyl, and the like; and acyloxy groups including:methoxycarbonyl, 9-fluorenyl-methoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl,vinyloxycarbonyl, allyloxycarbonyl, 1,1-dimethyl-propynyloxycarbonyl,benzyloxycarbonyl, p-nitrobenzyloxycarbony,2,4-dichlorobenzyloxycarbonyl, and the like. Representative carboxylprotecting groups include: methyl ester, however, it is not restrictedto other alkyl, benzylester, silyl ester, or substituted benzyl esters.Additional carboxyl protecting groups include: methyl-, ethyl-, andt-butyl-esters, trimethylsilyl, t-butyldimethylsilyl, diphenylmethyl,benzhydryl, cyanoethyl, 2-(trimethylsilyl)ethyl, nitroethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, and thelike. Suitable protecting groups and their respective uses are readilydetermined by one skilled in the art. For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

The term “leaving group” or “L”, as used herein, refers to the groupwith the meaning conventionally associated with it in synthetic organicchemistry, i.e., an atom or group displaceable under reaction (e.g.,alkylating) conditions. Examples of leaving groups include halo (e.g.,Cl, F, Br, I), alkyl (e.g., methyl and ethyl), thiomethyl, tosylates,mesylates, and the like. Preferably, the leaving group is a triflate oriodo group.

Schemes 1-5 outline the general procedures useful for the preparation ofcompounds of the present invention. It is to be understood, however,that the invention, as fully described herein and as recited in theclaims, is not intended to be limited by the details of the followingschemes or modes of preparation. Other reagents and preparatory modesknown by the skilled artisan can also be used. Further, the leavinggroup, L, the protecting groups, Pg¹ and Pg², X, Y, Z, R¹, R², and R³are as described herein. In Scheme 1, W represents an atom such ascarbon (C), nitrogen (N), or oxygen (O), preferably C or O, and theletter “m” refers to an integer with a value of 0, 1, or 2. The letter“L” refers to a leaving group which undergoes nucleophilic substitutionwith a nucleophile, and refers to a halogen (e.g., chlorine, bromine,fluorine, or iodide), triflate, mesylate, or tosylate, preferably atriflate. Further, the amino group is protected as a tert-butoxycarbonylprotecting group (Pg¹) and the carboxyl group is protected as amethyl-ester protecting group (Pg²).

Scheme 1 describes the preparation of chiral α-amino acids (1.5) andfinally to an activated ester (1.8) for introduction of an N-linkedheterocycle. Although, Scheme 1 describes a method for the preparationof compound (1.5), availability of this amino acid is not restricted tothis method only. Alpha-amino acids can also be prepared by othermethods known to the skilled artisan or can be purchased from commercialvendors (e.g., Sigma-Aldrich (St. Louis, Mo.); Acros Organics (Geel,Belgium); Fulcrum Scientific Limited (West Yorkshire, UK); and AmatekChemical (Kowloon, Hong Kong)). Amino ester (1.2) can be synthesizedfrom an appropriately functionalized amino-protected (N-Pg¹) andcarboxy-protected (O-Pg²) derivative (1.1) with a leaving group (L,preferably an iodo group (Jackson, R. F. W., et. al., Org. Syn., 81, 77,(2005)), by metal mediated coupling, for example, palladium. In apreferred example, 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonatecan be coupled with (R)-methyl2-(tert-butoxycarbonylamino)-3-iodopropanoate in the presence ofPdCl₂(PPh₃)₂ after treating the former with Zinc in an inert solventsuch as dimethyl-formamide. The olefin functionality in (1.2) can thenbe reduced to the corresponding saturated compound (1.3) underhydrogenation conditions. A typical hydrogenation reaction can beperformed in methanol with hydrogen in the presence of catalytic amountof Pd/C. Further removal of the amino-protecting group in (1.3) followedby removal of the carboxy protecting group of intermediate (1.4) affordsthe desired amino acid (1.5). For example, the tert-butoxycarbonylprotecting group and the methyl ester can be cleaved under acidiccondition (HCl) in water. The activated ester (1.8) can be synthesizedvia treatment with an activating agent such as trifluoromethanesulfonicanhydride from the α-hydroxy-ester (1.7) (Degerbeck, F., et. al., J.Chem. Soc., Perkin Trans. 1, 11-14, (1993)). In a typical procedure thisreaction can be performed in an inert solvent such as anhydrous CH₂Cl₂in the presence of mild base such as 2,6-lutidine by dropwise additionof trifluoromethanesulfonic anhydride to the hydroxy-ester (1.7). Theα-hydroxy-ester (1.7) can be prepared from the corresponding amino acid(1.5) via sequence of reactions, first by diazotization of the aminoacid with sodium nitrite in water in presence of acid (McCubbin, J. A.,et. al., Org. Letters, 8, 2993-2996, (2006)) followed by acid catalyzed(H₂SO₄) esterification of the resulting hydroxy-ester (1.6).

Scheme 2, describes the preparation of carboxy-protectedhetero-substituted-esters (2.4) and (2.7).

In Method A, the intermediate (2.3) can be obtained from commerciallyavailable halo-substituted heterocycles (2.1) by treatment witht-butyllithium followed by reaction with a dialkyl disulfide (Katritzky,Alan R. et al. J. Chem. Soc., Perkin Trans. 1, (6), 1139-45; 1989). Theresulting sulfide (2.2) can be oxidized to the corresponding sulfonewith a suitable oxidant such as potassium peroxomonosulfate (Oxone®,DuPont Specialty Chemicals (Deepwater, N.J.)), or m-chloroperoxybenzoicacid (See, e.g., Bernotas, Ronald et al. Bioorganic & MedicinalChemistry Letters, 14(22), 5499-5502; 2004; Kristof, T. J., et. al.,Tetrahedron, 63, Issue 36, 8954-8961, (2007), Kulkarni, Surendra et al.Australian Journal of Chemistry, 40(8), 1415-25; 1987). Intermediate(2.3) can be converted to (2.4) by nucleophilic substitution reaction.The nucleophilic substitution reaction can be performed in a chiralcompound with inversion of the stereochemistry at the chiral center. Thenucleophile can be generated by treatment of an appropriate intermediate(2.3) with lithium hexamethyldisilazide and subsequent addition of thetriflate-ester (1.8) thereby generating the carboxy-protected2-hetero-substituted-ester (2.4). Other suitable bases with anappropriate pK_(b) and other alkylating agents (e.g., alkyl sulfonatesand the like) can also be utilized (Effenberger, Franz et al. LiebigsAnnalen der Chemie, (2), 314-33; 1986; Terasaka, Tadashi et al.Bioorganic & Medicinal Chemistry Letters, 13(6), 1115-1118; 2003). Q isa halogen, preferably Br or I.

For example, 4-bromo-1H-imidazole (2.1) can be converted to4-(alkyllthio)-1H-imidazole (2.2) by treatment with t-butyllithiumfollowed by reaction with dialkyldisulfide. The sulfide moiety inintermediate (2.2) can be oxidized to corresponding sulfone (2.3) bytreatment with m-chloroperbenzoic acid in an inert solvent such asCH₂Cl₂. Methyl3-substituted-2-(4-(alkylsulfonyl)-1H-imidazol-1-yl)propanoate (2.4) wasthen synthesized from (2.3) by treatment with lithiumhexamethyldisilazide in an inert solvent such as THF followed byaddition of triflate-ester (1.8).

Further, compound (2.4) can be prepared via reversal of the reactionsequence as shown in Method B. In this case, the alkylation of a sulfidederivative (2.2) with (1.8) can be performed first, and the resultingintermediate (2.5) can be oxidized to the desired sulfone (2.4). Forexample, 4-substituted-1H-pyrazole (2.2) can be synthesized from4-bromo-1H-pyrazole (2.1) by metal-halogen exchange followed bytreatment with a dialkyl-disulfide (e.g. diisopropyl disulfide) in THFat low temperature. 4-substituted-1H-pyrazole (2.2) can be treated withlithium bis(trimethylsilyl)amide followed by treatment with theactivated ester (1.8) providingsubstituted-2-(4-(thioalkyl)-1H-pyrazol-1-yl)propanoate (2.5), which canbe further oxidized to the sulfone with potassium peroxomonosulfate(Oxone®, DuPont Specialty Chemicals, Deepwater, N.J., USA).

Finally, compound (2.7) can be prepared directly from the commerciallyavailable heterocycles (such as 3-(trifluoromethyl)-1H-pyrazole,(Shanghai Sinofluoro Scientific Corporation, Shanghai, China)) as shownin Method C using alkylation chemistry as described herein.

The final transformation to the amide (3.1) can be accomplished via anacid catalyzed transamidation reaction. For example, transformation ofthe α-heterocycle substituted ester (2.7, wherein the Pg² moietydepicted is methyl) to the amide (3.1) can be achieved by treatment witha Lewis acid in the presence of an appropriate amine (R⁴NH₂), alsoreferred to as an aprotic acid, such as AlMe₃ or AlMe₂Cl. See, e.g.,Yadav, J. S., et. al., Tet. Letters, 48, Issue 24, 4169-4172, (1977).Other suitable Lewis acids include Al₂O₃, TiO₂, ZnCl₂, SnCl₄, TiCl₄,FeCl₃, AlMe₃, AlMe₂Cl, and the like.

Alternatively, this transformation can be achieved via ester hydrolysisof the ester (2.7) to the corresponding carboxylic acid (3.2) underacidic or basic conditions and coupling with an appropriate amine toproduce the pyridone amide (i.e., a compound of the present invention).Hydrolysis of the ester can be performed under either basic or acidicconditions. For example, aqueous NaOH, KOH, or LiOH in the presence ofan inert organic solvent such as THF or dioxane can be used for basecatalyzed hydrolysis. For acid catalyzed hydrolysis, HCl in the presenceof water with or without an organic solvent can be used. See, e.g.,Puschl, A., et. al., J. Chem. Soc., Perkin Transactions 1, (21),2757-2763, (2001). Other suitable methods can be used to catalyze thehydrolysis. It is noted that compounds of Formula (2.4) can undergo asimilar acid catalyzed transamidation reaction or ester hydrolysis forthe final sulfonyl substituted amide transformation. The term “couplingreagent” refers to a chemical reagent that is commonly employed as anagent to couple or join two or more specific compounds to make a singlecombined compound. Suitable coupling agents include[O-(7-azabenzotriazol-1-yl)-N,N,N,Ar-tetramethyluroniumhexafluorophosphate], 1,1′-thiocarbonyldimidazole, and the like.Moreover, activation of the acid (3.2) to an acid chloride followed bytreatment of the suitable amine will also provide compound (3.1).

Scheme 4 describes an alternate preparation of the hydroxy-ester (1.7)(Alami, M., et. al., Tet. Asym., 8(17), 2949-2959, (1997). Li₂CuCl₄,prepared from CuCl₂ and LiCl in THF, can be added to a cold Grignardreagent solution in THF, for instance in a preferred examplecyclopentylmagnesium bromide, to form the alkyl magnesium cuprate. Uponaddition of (4.1), for instance methyl(2R)-glycidate, followed by anaqueous quench, (1.7) is formed.

Scheme 5 describes another route to synthesize compounds like (5.5).Intermediate (5.2) can be synthesized by the nucleophilic displacementof a leaving group, such as bromide, on (5.1) by the anion ofheterocycle (2.4) formed by mixing (2.4) with a base of sufficientstrength, such as sodium hydride (Liu, Z.-C., et al. Tetrahedron, 2005,61(33), 7967-7973.). An aldol condensation with an aldehyde can formalkene (5.3) via dehydration of a hydroxy intermediate (Sawyer, J. S. J.Med. Chem. 2005, 48, 893-896.). This reaction is promoted by a base suchas potassium tert-butoxide. Reduction of the double bond can form (5.4).This can be accomplished with methods that include Pd/C, hydrogen gas ortransfer hydrogenation, whereby a hydrogen source other than hydrogengas is used, for example ammonium formate in the presence of Pd/C (Ranu,B. C., et al. J. Indian Chem. Soc. 1998, 75(10-12), 690-694.). Forming(5.5) can be accomplished as detailed in Scheme 3 either directly or viathe carboxylic acid.

A compound of the present invention may be isolated and used per se oroptionally administered in the form of its pharmaceutically acceptablesalt, hydrate, and/or solvate. For example, it is well within the scopeof the present invention to convert the compounds of the presentinvention into and use them in the form of their pharmaceuticallyacceptable salts derived from various organic and inorganic acids andbases, acids of amino acids, salts derived form organic and inorganicacids and cationic salts based on the alkali and alkaline earth metalsin accordance with procedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydrofluoride,hydroiodide; other mineral acids and their corresponding salts such assulfate, nitrate, phosphate; and alkyl and monoarysulfonates such asethanesulfonate, toluenesulfonate, and benzene sulfonate; and otherorganic acids and their corresponding salts such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. Such salts include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, trifluoroacetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, acetate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,malate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate, gluconate, galacturonate, and thelike. See, e.g., Berge S. M., et. al., Pharmaceutical Salts, J. ofPharma. Sci., 66:1 (1977).

Compounds of the present invention that comprise basicnitrogen-containing groups may be quaternized with such agents as(C₁-C₄)alkyl halides, e.g., methyl, ethyl, isopropyl, and tert-butylchlorides, bromides, and iodides; di-(C₁-C₄)alkyl sulfates, e.g.,dimethyl, diethyl, and diamyl sulfates; (C₁₀-C₁₈)alkyl halides, e.g.,decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, andiodides; and aryl(C₁-C₄)alkyl halides, e.g., benzylchloride andphenethyl bromide. Such salts permit the preparation of bothwater-soluble and oil-soluble compounds of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable organic or inorganic base. Non-exclusive examples of baseaddition salts include, but are not limited to alkali metal hydroxidesincluding potassium, sodium, and lithium hydroxides; alkaline earthmetal hydroxides such as barium and calcium hydroxides; alkali metalalkoxides, e.g., potassium ethanolate and sodium propanolate; andvarious organic bases such as ammonium hydroxide, piperidine,diethanolamine and N-methylglutamine. Also included are aluminum saltsof the compounds of the present invention. Further base salts of thepresent invention include, but are not limited to: copper, ferric,ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, andzinc salts. Organic base salts include but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, e.g., ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, and ethylamine;and basic ion exchangeresins, e.g., arginine, betaine, caffeine, chloroprocaine, choline,N,N′-dibenzylethylenediamine, dicyclohexylamine, diethanolamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, andglucosamine. See, e.g., Berge S. M., et. al., Pharmaceutical Salts, J.of Pharma. Sci., 66:1, (1977). It should be recognized that the freeacid forms will typically differ from their respective salt formssomewhat in physical properties such as solubility in polar solvents,but otherwise the salts are equivalent to their respective free acidforms for the purposes of the present invention.

All of the salt forms are within the scope of the compounds useful inthe method of the present invention. Conventional concentration orcrystallization techniques can be employed to isolate the salts.

The compounds and salts of the present invention may inherently formsolvates, including hydrated forms, with pharmaceutically acceptablesolvents. A solvate refers to a molecular complex of a compoundrepresented by Formula (1A) including pharmaceutically acceptable saltsthereof, with one or more solvent molecules. In general, the solvatedforms, including hydrated forms, are equivalent to unsolvated forms andare intended to be encompassed within the scope of the presentinvention. Solvents that are commonly used in the pharmaceutical art,which are known to be innocuous to the recipient include water, ethanol,methanol, isopropanol, dimethylysulfoxide (DMSO), ethyl acetate, aceticacid, or ethanolamine, and the like. Although pharmaceuticallyacceptable solvents are preferred, other solvents may be used and thendisplaced with a pharmaceutically acceptable solvent to acquire certainpolymorphs. A hydrate refers to the complex where the solvent moleculeis water. Solvates, including hydrates, are considered compositions ofthe compound of the present invention.

It is also possible that the intermediates and compounds of the presentinvention may exist in different tautomeric forms. Tautomers refer toorganic compounds that are interconvertible, i.e., when a chemicalreaction results in a formal migration of a proton accompanied by aswitch of a single bond and adjacent double bond (e.g., enol/keto,amide/imidic acid, and amine/imine forms) or as illustrated below

See, e.g., Katritzky, A. R., et. al., The Tautomerism of Heterocycles,Academic Press, New York, (1976). All such tautomeric forms are embracedwithin the scope of the invention.

The present invention also includes isotopically-labelled compounds,which are identical to those recited for the compound of Formula (1A),but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine,iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O,¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹²³I, ¹²⁵I and ³⁶Cl, respectively. Compounds ofFormula (1A) which contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of this invention.

Certain isotopically-labelled compounds of the present invention, forexample those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.

Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸F are useful forpositron emission tomography (PET) studies to examine substrateoccupancy. Isotopically labeled compounds of this invention thereof cangenerally be prepared by carrying out the procedures disclosed herein,by substituting a readily available isotopically labelled reagent for anon-isotopically labeled reagent.

Compounds of the present invention are useful for treating diseases,conditions and/or disorders mediated by the activation of glucokinase;therefore, another embodiment of the present invention is apharmaceutical composition comprising a therapeutically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient, diluent orcarrier. The compounds of the present invention (including thecompositions and processes used therein) may also be used in themanufacture of a medicament for the therapeutic applications describedherein.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water, and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations can be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent)) is dissolved in a suitable solvent in the presence of one ormore of the excipients described above. The compound of the presentinvention is typically formulated into pharmaceutical dosage forms toprovide an easily controllable dosage of the drug and to give thepatient an elegant and easily handled product.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present invention further provides a method of treating diseases,conditions and/or disorders mediated by the activation of glucokinase ina mammal that includes administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition comprising aneffective amount of a compound of the present invention and apharmaceutically acceptable excipient, diluent, or carrier. The methodis particularly useful for treating diseases, conditions and/ordisorders that benefit from the activation of glucokinase which include:eating disorders (e.g., binge eating disorder, anorexia, bulimia, weightloss or control and obesity), prevention of obesity and insulinresistance by glucokinase expression in skeletal muscle of transgenicmice (Otaegui, P. J., et. al., The FASEB Journal, 17; 2097-2099,(2003)); and Type II diabetes, insulin resistance syndrome, insulinresistance, and hyperglycemia (Poitout, V., et. al., “An integrated viewof β-cell dysfunction in type-II diabetes”, Annul. Rev. Medicine, 47;69-83, (1996)).

One aspect of the present invention is the treatment of Type IIdiabetes, progression of disease in Type II diabetes, metabolic syndrome(Syndrome X or a combination of elevated blood glucose, hypertension,obesity, decreased HDL cholesterol, and elevated triglycerides),hyperglycemia, impaired glucose tolerance (a pre-diabetic state ofdysglycemia associated with insulin resistance), glucosuria (abnormalcondition of osmotic diuresis due to excretion of glucose by thekidneys), cataracts, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, obesity; conditions exacerbated by obesity; hypertension;dyslipidemia; hyperinsulinemia (excess circulating blood insulin oftenassociated with metabolic syndrome and NIDDM), and diabetic macularedema. The preferred disease, disorder, or condition to be treated isType II diabetes, hyperglycemia, and reducing blood glucose. Mostpreferred is Type II diabetes.

Diabetes is generally defined as a syndrome characterized by disorderedmetabolism and inappropriately high blood glucose (hyperglycemia)resulting from either low levels of the hormone insulin or from abnormalresistance to insulin's effects coupled with inadequate levels ofinsulin secretion to compensate. Diabetes is generally characterized asthree main forms: (1) Type I, (2) Type II, and (3) gestational diabetes.Type I diabetes is usually due to autoimmune destruction of thepancreatic beta cells. Type II diabetes is characterized by insulinresistance in target tissues. This causes a need for abnormally highamounts of insulin and diabetes develops when the beta cells cannot meetthis demand. Gestational diabetes is similar to Type II diabetes in thatit involves insulin resistance; the hormones of pregnancy can causeinsulin resistance in women genetically predisposed to developing thiscondition, and typically resolves with delivery of the child. However,Types I and II are chronic conditions. Type 1 diabetes, in which insulinis not secreted by the pancreas, is directly treatable with insulin,although dietary and other lifestyle adjustments are part of diseasemanagement. Type II diabetes may be managed with a combination of dietand pharmaceutical products (e.g., medicaments), and frequently, insulinsupplementation. Diabetes can cause many complications. Acutecomplications include hypoglycemia, hyperglycemia, ketoacidosis ornonketotic hyperosmolar coma. Serious long-term complications include,but are not limited to: cardiovascular disease, renal failure, retinaldamage, decreased blood circulation, nerve damage, and hypertension.

In yet another aspect of the present invention is the treatment ofdiabetes related disorders, such as metabolic syndrome. Metabolicsyndrome includes diseases, conditions or disorders such asdyslipidemia, hypertension, insulin resistance, coronary artery disease,obesity, and heart failure. For more detailed information on MetabolicSyndrome, see, e.g., Zimmet, P. Z., et al., “The Metabolic Syndrome:Perhaps an Etiologic Mystery but Far From a Myth—Where Does theInternational Diabetes Federation Stand?,” Diabetes & Endocrinology,7(2), (2005); and Alberti, K. G., et al., “The Metabolic Syndrome—A NewWorldwide Definition,” Lancet, 366, 1059-62 (2005). Preferably,administration of the compounds of the present invention provides astatistically significant (p<0.05) reduction in at least onecardiovascular disease risk factor, such as lowering of plasma leptin,C-reactive protein (CRP) and/or cholesterol, as compared to a vehiclecontrol containing no drug. The administration of compounds of thepresent invention may also provide a statistically significant (p<0.05)reduction in glucose serum levels.

For a normal adult human having a body weight of about 100 kg, a dosagein the range of from about 0.001 mg to about 10 mg per kilogram bodyweight is typically sufficient, preferably from about 0.01 mg/kg toabout 5.0 mg/kg, more preferably from about 0.01 mg/kg to about 1 mg/kg.However, some variability in the general dosage range may be requireddepending upon the age and weight of the subject being treated, theintended route of administration, the particular compound beingadministered and the like. The determination of dosage ranges andoptimal dosages for a particular patient is well within the ability ofone of ordinary skill in the art having the benefit of the instantdisclosure. It is also noted that the compounds of the present inventioncan be used in sustained release, controlled release, and delayedrelease formulations, which forms are also well known to one of ordinaryskill in the art.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents for the treatment of the diseases,conditions and/or disorders described herein. Therefore, methods oftreatment that include administering compounds of the present inventionin combination with other pharmaceutical agents are also provided.Suitable pharmaceutical agents that may be used in combination with thecompounds of the present invention include anti-obesity agents(including appetite suppressants), anti-diabetic agents,anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensiveagents.

Suitable anti-obesity agents include cannabinoid-1 (CB-1) antagonists(such as rimonabant), 11β-hydroxy steroid dehydrogenase-1 (11β-HSDtype 1) inhibitors, stearoyl-CoA desaturase-1 (SCD-1) inhibitor, MCR-4agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptakeinhibitors (such as sibutramine), sympathomimetic agents, β₃ adrenergicagonists, dopamine agonists (such as bromocriptine),melanocyte-stimulating hormone analogs, 5HT2c agonists, melaninconcentrating hormone antagonists, leptin (the OB protein), leptinanalogs, leptin agonists, galanin antagonists, lipase inhibitors (suchas tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as abombesin agonist), neuropeptide-Y antagonists (e.g., NPY Y5antagonists), PYY₃₋₃₆ (including analogs thereof), thyromimetic agents,dehydroepiandrosterone or an analog thereof, glucocorticoid agonists orantagonists, orexin antagonists, glucagon-like peptide-1 agonists,ciliary neurotrophic factors (such as Axokine™ available from RegeneronPharmaceuticals, Inc., Tarrytown, N.Y. and Procter & Gamble Company,Cincinnati, Ohio), human agouti-related protein (AGRP) inhibitors,ghrelin antagonists, histamine 3 antagonists or inverse agonists,neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTPinhibitors, such as dirlotapide), opioid antagonist, orexin antagonist,and the like.

Preferred anti-obesity agents for use in the combination aspects of thepresent invention include CB-1 antagonists (e.g., rimonabant,taranabant, surinabant, otenabant, SLV319 (CAS No. 464213-10-3) andAVE1625 (CAS No. 358970-97-5)), gut-selective MTP inhibitors (e.g.,dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) andCAS No. 913541-47-6), CCKa agonists (e.g.,N-benzyl-2-[4-(1H-indol-3-ylmethyl)-5-oxo1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamidedescribed in PCT Publication No. WO 2005/116034 or US Publication No.2005-0267100 A1), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g.,compounds described in U.S. Pat. No. 6,818,658), lipase inhibitor (e.g.,Cetilistat), PYY₃₋₃₆ (as used herein “PYY₃₋₃₆” includes analogs, such aspeglated PYY₃₋₃₆ e.g., those described in US Publication 2006/0178501),opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No.180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine(NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide(Byetta®), AOD-9604 (CAS No. 221231-10-3) and sibutramine. Preferably,compounds of the present invention and combination therapies areadministered in conjunction with exercise and a sensible diet.

Suitable anti-diabetic agents include an acetyl-CoA carboxylase-2(ACC-2) inhibitor, a phosphodiesterase (PDE)-10 inhibitor, adiacylglycerol acyltransferase (DGAT) 1 or 2 inhibitor, a sulfonylurea(e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide,glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone,glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylaseinhibitor (e.g., tendamistat, trestatin and AL-3688), an α-glucosidehydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g.,adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q,and salbostatin), a PPARγ agonist (e.g., balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone andtroglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929,GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide(e.g., metformin), a glucagon-like peptide 1 (GLP-1) agonist (e.g.,exendin-3 and exendin-4), a protein tyrosine phosphatase-1 B (PTP-1B)inhibitor (e.g., trodusquemine, hyrtiosal extract, and compoundsdisclosed by Zhang, S., et al., Drug Discovery Today, 12 (9/10), 373-381(2007)), SIRT-1 inhibitor (e.g., reservatrol), a dipeptidyl peptidase IV(DPP-IV) inhibitor (e.g., sitagliptin, vildagliptin, alogliptin andsaxagliptin), an insulin secreatagogue, a fatty acid oxidationinhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK)inhibitor, insulin, an insulin mimetic, a glycogen phosphorylaseinhibitor, a VPAC2 receptor agonist and a glucokinase activator.Preferred anti-diabetic agents are metformin and DPP-IV inhibitors(e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin).

Suitable antihyperglycemic agents include, but are not limited to,alpha-glucosidase inhibitors (i.e., acarbose), biguanides, insulin,insulin secretagogues (i.e., sulfonureas (i.e., gliclazide, glimepiride,glyburide) and nonsulfonylureas (i.e., nateglinide and repaglinide)),thiazolidinediones (i.e. pioglitazone, rosiglitazone), and the like.

Suitable lipid lowering agents include, but are not limited to, HMGCoAreductase inhibitors, fibrates, microsomal triglyceride transfer proteininhibitors, cholesterol transfer protein inhibitors, acyl transferprotein inhibitors, low density lipid antioxidants, and the like.

Suitable antihypertensive agents include, but are not limited to,diuretics, adrenergic beta-antagonists, adrenergic alpha-antagonists,angiotensin-converting enzyme inhibitors, calcium channel blockers,ganglionic blockers, vasodilators, and the like.

According to the methods of the invention, when a compound of thepresent invention and at least one other pharmaceutical agent areadministered together, such administration can be sequential in time orsimultaneous with the simultaneous method being generally preferred. Forsequential administration, a compound of the present invention and theadditional pharmaceutical agent can be administered in any order. It isgenerally preferred that such administration be oral. It is especiallypreferred that such administration be oral and simultaneous. When acompound of the present invention and the additional pharmaceuticalagent are administered sequentially, the administration of each can beby the same or by different methods, for example, tablet and syrup orcapsule and parenteral injection or infusion. Administration and dosingwill be determined by the prescribing practitioner.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.),Sigma-Aldrich (St. Louis, Mo.), Acros Organics (Geel, Belgium), orLancaster Synthesis Ltd. (Morecambe, United Kingdom) or may be preparedby methods well known to a person of ordinary skill in the art,following procedures described in such standard references as Fieser andFieser's Reagents for Organic Synthesis, Vols. 1-17, John Wiley andSons, New York, N.Y., (1991); Rodd's Chemistry of Carbon compounds,Vols. 1-5 and supps., Elsevier Science Publishers, (1989); OrganicReactions, Vols. 1-40, John Wiley and Sons, New York, N.Y., (1991);March J., Advanced Organic Chemistry, 4th ed., John Wiley and Sons, NewYork, N.Y.; and Larock, Comprehensive Organic Transformations, VCHPublishers, New York, (1989). Anhydrous tetrahydrofuran (THF), methylenechloride (CH₂Cl₂), and N,N-dimethylformamide may be purchased fromAldrich in Sure-Seal bottles and used as received. Solvents may bepurified using standard methods known to those skilled in the art,unless otherwise indicated. Further, starting materials were obtainedfrom commercial suppliers and used without further purification, unlessotherwise indicated.

The reactions set forth below were done generally under a positivepressure of argon or nitrogen or with a drying tube, at ambienttemperature (unless otherwise stated), in anhydrous solvents, and thereaction flasks were fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. Analytical thin layer chromatography (TLC) was performedusing glass-backed silica gel 60 F 254 precoated plates (Merck Art 5719)and eluted with appropriate solvent ratios (v/v). Reactions were assayedby TLC or LCMS and terminated as judged by the consumption of startingmaterial. Visualization of the TLC plates was done with UV light (254 nMwavelength) or with an appropriate TLC visualizing solvent and activatedwith heat. Flash column chromatography (Still et al., J. Org. Chem. 43,2923, (1978)) was performed using silica gel 60 (Merck Art 9385) orvarious MPLC systems, such as Biotage or ISCO purification system.

Conventional methods and/or techniques of separation and purificationknown to one of ordinary skill in the art can be used to isolate thecompounds of the present invention, as well as the various intermediatesrelated thereto. Such techniques will be well-known to one of ordinaryskill in the art and may include, for example, all types ofchromatography (high pressure liquid chromatography (HPLC), columnchromatography using common adsorbents such as silica gel, andthin-layer chromatography (TLC)), recrystallization, and differential(i.e., liquid-liquid) extraction techniques. Biotage materials werepurchased from Biotage AB (Charlottesville, Va.).

The compound structures in the Examples below were confirmed by one ormore of the following methods: proton magnetic resonance spectroscopy,mass spectroscopy, and elemental microanalysis. Proton magneticresonance (¹H NMR) spectra were determined using a Bruker or Varianspectrometer operating at a field strength of 300 or 400 megahertz(MHz). Chemical shifts are reported in parts per million (PPM, δ)downfield from an internal tetramethylsilane standard. Alternatively, ¹HNMR spectra were referenced to signals from residual protons indeuterated solvents as follows: CDCl₃=7.25 ppm; DMSO-d₆=2.49 ppm;C₆D₆=7.16 ppm; CD₃OD=3.30 ppm. Mass spectra (MS) data were obtainedusing Agilent mass spectrometer or Waters Micromass spectrometer withatmospheric pressure chemical or electron spray ionization. Method:Acquity UPLC with chromatography performed on a Waters BEH C18 column(2.1×30 mm, 1.75 μm) at 60° C. The mobile phase was a binary gradient ofacetonitrile (containing 0.05% trifluoroacetic acid) and water (5-95%)Elemental microanalyses were performed by Atlantic Microlab Inc. andgave results for the elements stated within ±0.4% of the theoreticalvalues.

Embodiments of the present invention are illustrated by the followingExamples. It is to be understood, however, that the embodiments of theinvention are not limited to the specific details of these Examples, asother variations thereof will be known, or apparent in light of theinstant disclosure, to one of ordinary skill in the art.

All of the above recited U.S. patents and publications are incorporatedherein by reference.

Preparation of Key Intermediates

The following intermediates provide a more detailed description of theprocess conditions. It is to be understood, however, that the invention,as fully described herein and as recited in the claims, is not intendedto be limited by the details of the following schemes or modes ofpreparation. In the following intermediates, Boc refers to1-tert-butyloxycarbonyl, and Tf refers to triflate.

Intermediate: (R)-methyl 3-cyclopentyl-2-hydroxypropanoic acid (I-1a)

To a stirred solution of (R)-2-amino-3-cyclopentylpropanoic acid (5.0grams; Chem-Impex International, Inc., Wood Dale, Ill.) and 1 M H₂SO₄(45.1 mL) at 0° C., was added a solution of NaNO₂ (3.12 g) in H₂O (15.6mL) drop wise over 10 minutes. The reaction mixture was stirred for 3hours at 0° C., then for 2 hours at room temperature. The solution wasthen extracted (3 times) with diethyl ether. The combined organicextracts were dried over MgSO₄, filtered, and the filtrate concentratedto afford 2.36 g of (I-1a). ¹H NMR (400 MHz, CDCl₃) δ 4.26-4.28 (1H),1.99-2.07 (1H), 1.76-1.81 (4H), 1.60-1.62 (4H), 1.12-1.16 (2H); LCMS forC₈H₁₄O₃ m/z 157.1 (M−H)⁻.

Intermediate: (R)-methyl 3-cyclopentyl-2-hydroxypropanoate (I-1b)

To a stirred solution of 2.36 g of (I-1a) in anhydrous methanol (15 mL)at room temperature was added SOCl₂(1.64 mL). The resulting mixture washeated at reflux for 2 hours. It was then cooled and concentrated underreduced pressure. The residue was partitioned between ethyl acetate andaqueous saturated NaHCO₃ solution. The biphasic mixture was separatedand the aqueous portion was extracted with ethyl acetate. The combinedextracts were dried over MgSO₄, filtered, and the filtrate concentratedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography (silica gel, heptanes/ethyl acetate) to afford 1.5g of (I-1b) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 4.15-4.20 (1H),3.77 (3H), 2.62-2.63 (1H), 1.97-2.05 (1H), 1.49-1.86 (8H), 1.06-1.17(2H); LCMS for C₉H₁₆O₃ m/z 171.6 (M)⁺. Intermediate (I-1b) canalternatively be prepared by the method described below.

A 0.2M solution of Li₂CuCl₄ was prepared as follows: Anhydrous CuCl₂(26.9 g, 200 mol) and anhydrous LiCl (17.0 g, 400 mmol) were dissolvedin THF (1000 mL). The mixture required gentle heating to completelydissolve the solids. After cooling the solution is ready for use.

A solution of Li₂CuCl₄ (0.2 M in THF, 125 mL, 25.0 mmol) was addedslowly to a suspension of cyclopentylmagnesium bromide (2 M in diethylether, 135 mL, 270 mmol; Aldrich Chemical Company, Inc., Milwaukee,Wis.) and THF (500 mL) at −50° C. over 2-3 mins. The pale grey/brownsuspension was then allowed to warm slowly to −10° C. over 30 mins, bywhich time the color had developed to a dark grey. The mixture wasre-cooled to −78° C. and (R)-methyl oxirane-2-carboxylate (25.0 g, 245mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added neatvia syringe over 90 seconds. The reaction was then stirred at −78° C.for 20 mins, before removing the ice-bath and allowing to warm toapproximately −50° C. over 30 mins. Saturated NH₄Cl (aq, 700 mL) wasthen added and the mixture stirred for 30 mins. The organic layer wascollected and the aqueous layer extracted with diethyl ether (2×250 mL).The combined organics were washed with saturated NH₄Cl (aq, 350 mL),dried over MgSO₄, and evaporated. Distillation of the crude residue(68-70° C. at 0.8 mbar) yielded 65-70% of (I-1b) as a pale yellow oil. Asmall amount of less volatile material remained in the still pot. ¹H NMR(400 MHz; CDCl₃): δ 4.17 (1H), 3.76 (3H), 2.67 (1H), 2.01 (1H),1.48-1.88 (8H), 1.11 (2H).

Intermediate: (R)-methyl3-cyclopentyl-2-(trifluoromethylsulfonyloxy)propanoate (I-1c)

Intermediate (I-1b) (6.37 g, 37.0 mmol) was dissolved in drydichloromethane (260 mL) and stirred under nitrogen in an ice bath.2,6-Lutidine (9.0 mL, 77 mmol) was added. Trifluoromethanesulfonic acidanhydride (11 mL, 65 mmol) in dry dichloromethane (75 mL) was addeddropwise. The reaction was stirred in the ice bath for 60 minutes,concentrated under reduced pressure, and taken up in 1N HCl and methylt-butyl ether. The aqueous layer was separated, and the organic layerwas washed with additional 1N HCl to insure the removal of all thelutidine. The combined organic layer was then washed with brine, driedover sodium sulfate, filtered, concentrated under reduced pressure, anddried under high vacuum to afford (I-1c) (11.3 g, 37 mmol, 100%), whichwas used immediately without further purification; ¹H NMR (400 MHz,CDCl₃) δ 5.10-5.14 (1H), 3.82 (3H), 2.02-2.12 (1H), 1.79-1.98 (4H),1.51-1.66 (4H), 1.08-1.18 (2H).

Intermediate: 4-(isopropylthio)-1H-pyrazole (I-2a)

To a stirred solution of 4-bromo-1H-pyrazole (2.49 g, 16.9 mmol; AldrichChemical Company, Inc., Milwaukee, Wis.) in THF under nitrogen at 0° C.was added dropwise n-butyllithium (34.9 mL, 1.6 M in hexanes). Thereaction mixture was slowly warmed to room temperature and stirred for 1hour. It was then cooled to 0° C., diisopropyl disulfide (2.70 mL, 16.9mmol) was added dropwise and stirring continued at the same temperaturefor 2 hours. The reaction mixture was poured into a biphasic mixture of100 mL ethyl acetate and 50 mL ice water. The pH of the mixture wasadjusted to about 6 and the organic portion was separated, washed withwater, brine and dried over MgSO₄. It was then filtered and the filtratewas concentrated under reduced pressure to afford 1.88 g of (I-2a).

Intermediate: (S)-methyl3-cyclopentyl-2-(4-(isopropylthio)-1H-pyrazol-1-yl)propanoate (I-3a)

To a stirred solution of 124 mg of (I-2a) in 9 mL of anhydrous THF undernitrogen, a solution of lithium bis(trimethylsilyl)amide (0.784 mL, 1 Min hexanes) was added. After 45 minutes, a solution of Intermediate(I-1c) (265 mg in 6 mL of anhydrous THF) was added dropwise and stirringcontinued for 2 hours at room temperature. It was then quenched withaqueous saturated NH₄Cl and extracted with ethyl acetate. The combinedorganic extracts were dried over MgSO₄, filtered, and concentrated. Theresulting residue was purified by flash chromatography (silica gel,0-100% ethyl acetate in heptane) to afford (I-3a), m/z 297.1 (M+H)⁺.

Intermediate: (S)-methyl3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)propanoate(I-4a1)

To a stirred solution of 0.157 g (I-3a) in 5 mL dichloromethane at 0° C.was added trifluoroacetic acid (0.041 mL) followed by m-chloroperbenzoicacid (0.229 g). After 30 minutes, the ice bath was removed and thereaction stirred at room temperature for another 30 minutes beforepartitioning between ethyl acetate and aqueous saturated NaHCO₃. Theaqueous portion was extracted with ethyl acetate and the combinedorganics were dried over MgSO₄. It was then filtered and the filtrateconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography (silica gel, 0-100% ethyl acetate inheptane) to afford 0.167 g of (I-4a1) as a white solid, m/z 329.2(M+H)⁺.

Intermediates (S)-methyl3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanoate (I-4a2)(m/z 301.2 (M+H)⁺) and (S)-methyl3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-pyrazol-1-yl)propanoate (I-4a3)(m/z 315.4 (M+H)⁺) were prepared in an analogous manner to thatdescribed for the synthesis of Intermediate (I-4a1) from4-bromo-1H-pyrazole using appropriate starting materials (e.g., dimethyldisulfide or diethyl disulfide, respectively.

Intermediate: 3-(methylsulfonyl)-1H-1,2,4-triazole (I-5a)

To a stirred solution of 3-methylthio-4H-1,2,4-triazole (1.00 g; OakwoodProducts, Inc., West Columbia, S.C.) in THF (20 mL) and water (20 mL)was added potassium peroxomonosulfate (Oxone®, DuPont SpecialtyChemicals, Deepwater, N.J., USA) (10.7 g). After stirring at roomtemperature for a day, the reaction mixture was filtered and thefiltercake was washed with THF. The filtrate was partitioned betweenwater and ethyl acetate, the bilayer was separated and the aqueousportion was extracted twice with ethyl acetate. The combined organicextracts were dried over MgSO₄, filtered, and the filtrate concentratedunder reduced pressure. The resulting residue was purified by flashchromatography (SiO₂, ethyl acetate/methanol, 0-10%) to afford 0.496 gof (I-5a) as a white solid. m/z 148.1 (M+H)⁺.

Intermediate: (S)-methyl3-cyclopentyl-2-(3-(methylsulfonyl)-1H-1,2,4-triazol-1-yl)propanoate(I-5b)

To a stirred solution of 42.7 mg of (I-5a) in anhydrous THF (4 mL) undernitrogen was added lithium bis(trimethylsilyl)amide (0.261 mL, 1 M inTHF). After stirring for 30 minutes, a solution of Intermediate (I-1c)(88.3 mg) in anhydrous THF (10 mL) was added dropwise. After 1 hour, thereaction was quenched with water, brine was added, and extracted withethyl acetate twice. The combined organics were dried over MgSO₄ andpurified by flash chromatography (40+M, 75:25, 60:40, 50:50, 0:100heptane:ethyl acetate) to give 0.0447 g of (I-5b) as a clear oil; m/z302.2 (M+H)⁺

Intermediate: 4-(isopropylthio)-1H-imidazole (I-6a)

To a stirred solution of 4-bromo-1H-imidazole (5.0 g; Aldrich ChemicalCompany, Inc., Milwaukee, Wis.) in 100 mL anhydrous THF at −78° C. in anoven dried 500 mL 3 necked-round bottom flask was added t-butyl-lithium(48.0 mL, 1.7 M in pentane) dropwise over 45 minutes with a droppingfunnel. After complete addition, the mixture was warmed to about 10° C.to 15° C. for 2 hours and then it was cooled to −78° C., and a cold(−78° C.) solution of diisopropyl disulfide (6.78 mL) in 30 mL THF wasadded via cannula. The reaction was stirred for 16 hours allowing thebath to warm. The pale yellow solution was quenched with saturated NH₄Clfollowed by neutralization with 10% HCl. The layers were separated andthe aqueous extracted with THF three times. The combined organics weredried over MgSO₄ and purified by flash chromatography (40+M, 100:0,95:5, 90:10 ethyl acetate/methanol) to afford 3.3767 g of (I-6a); m/z143.0 (M+H)⁺.

Intermediate: 4-(isopropylsulfonyl)-1H-imidazole (I-6b)

To a stirred solution of 1.00 g (I-6a) in dichloromethane (14 mL) at 0°C. was added trifluoroacetic acid (0.54 mL) followed bym-chloroperbenzoic acid (6.07 g) was added in portions. An additional 10mL dichloromethane was added to the mixture and stirring continued.After 20 minutes, the ice bath was removed and the reaction stirred atroom temperature for another 30 minutes before adding 1 equivalent of 1NNaOH (7.03 mL). The mixture was concentrated and the residue purified byflash column chromatography (SiO₂, ethyl acetate/heptane 0 to 10%) toafford 1.19 g of (I-6b); m/z 175.1(M+H)⁺.

Intermediate: (S)-methyl3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)propanoate(I-7a1)

To a stirred solution of 50 mg of (I-6a) in anhydrous THF (4 mL) undernitrogen was added lithium bis(trimethylsilyl)amide (0.260 mL, 1 M inTHF). After stirring for 30 minutes, a solution of Intermediate (I-1c)(88 mg in 3 mL anhydrous THF) was added dropwise. After 75 minutes, thereaction was quenched with water, brine was added, and extracted withethyl acetate twice. The combined organics were dried over MgSO₄ andpurified by flash chromatography (SiO₂, ethyl acetate/heptane, 25 to100%) to afford 53 mg of (I-7a1); m/z 329.1 (M+H)⁺.

Intermediates (S)-methyl3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)propanoate (I-7a2)m/z 315.4 (M+H)⁺ and (S)-methyl3-cyclopentyl-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanoate (I-7a3)m/z 301.4 (M+H)⁺ were prepared in an analogous manner to that describedfor the synthesis of Intermediate I-7a1, above, from4-bromo-1H-imidazole using appropriate starting materials (e.g., diethyldisulfide or dimethyl disulfide, respectively).

Intermediate: (S)-methyl3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate (I-8a)

4-Trifluoromethyl-1H-imidazole (5.0 g, 37.0 mmol; Apollo ScientificLtd., Bredbury, Cheshire, UK) was stirred in dry THF (180 mL) undernitrogen at room temperature. Lithium hexamethyldisilazide (1 M in THF,33.4 mL, 33.4 mmol) was added dropwise via addition funnel. The mixturewas stirred at room temperature for 50 minutes and then chilled in anice bath. A solution of (I-1c) (11.3 g, 37 mmol) in dry THF (45 mL),which had been chilled in an ice bath, was added in one portion. Thereaction was allowed to warm to room temperature, stirred for 2 hours,quenched with saturated aqueous ammonium chloride solution (20 mL) andallowed to stir overnight. The aqueous layer was separated, and theorganic layer was concentrated and then diluted with water and ethylacetate. The organic layer was washed in series with dilute aqueousphosphoric acid, aqueous 10% potassium carbonate, and brine. The organiclayer was then dried over sodium sulfate, filtered, and concentratedunder reduced pressure to a brown oil. The crude material, containingthe undesired regioisomer as a small impurity, was purified bychromatography on a 330 g pre-packed silica gel column, eluting with 10%ethyl acetate/heptane, linear gradient to 70% ethyl acetate/heptane. Theproduct fractions were located by spotting on a silica TLC plate andvisualizing with KMnO₄ stain. TLC (1:1 ethyl acetate/heptane, developedin potassium permanganate) located the pure and mixed fractions. Theclean product fractions were combined, evaporated, and dried under highvacuum to afford (I-8a) as a clear oil (6.61 g, 22.4 mmol, 67%). ¹H NMR(400 MHz, CDCl₃) δ 7.57 (1H), 7.38 (1H), 4.71-4.74 (1H), 3.76 (3H),2.01-2.14 (2H), 1.45-1.79 (7H), 1.03-1.18 (2H); m/z 291.4 (M+H)⁺.

Intermediate:(S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoic acid(I-8b)

6N HCl (140 mL) was added to (I-8a) (6.61 g, 22.4 mmol) and the mixturewas warmed to 95° C. for 16 hours and then allowed to cool. Solidpotassium carbonate (58 g) was added in portions to bring the pH toabout 4. A precipitate crashed out. Ethyl acetate was added, and themixture was stirred until everything dissolved. The aqueous layer wasextracted once with ethyl acetate. The combined organics were washedwith brine, dried over sodium sulfate, filtered, concentrated underreduced pressure, and dried under high vacuum to afford (I-8b) as aclear glass (6.15 g, 21.9 mmol, 98%). ¹H NMR (400 MHz, CDCl₃) δ 7.73(1H), 7.34 (1H), 6.85-7.15 (1H), 4.66-4.70 (1H), 1.98-2.17 (2H),1.41-1.75 (7H), 1.01-1.19 (2H); m/z 277.4 (M+H)⁺.

Intermediate:(S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoylchloride (I-8c)

To a suspension of intermediate (I-8b) (0.25 g, 0.9 mmol) indichloromethane (5 mL) was added oxalyl chloride (0.35 g, 2.7 mmol) andN,N-dimethylformamide (1 drop) at room temperature. The mixture wasstirred for 2 hours at room temperature. The reaction mixture wasconcentrated in vacuo, and the residue was chased with dichloromethanetwo times and concentrated in vacuo to afford (I-8c) (0.27 g, 100%) asan oil, which was used in the next step directly.

Intermediate: (S)-methyl3-cyclopentyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propanoate (I-9a1)

To a stirred solution of 3-(trifluoromethyl)-1H-pyrazole (500 mg, 3.67mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in 10 mL ofanhydrous THF under nitrogen was added a solution of lithiumhexamethyldisilazide (3.30 mL, 1 M in hexanes, 3.3 mmol). After stirringfor 40 minutes at room temperature, a solution of Intermediate (I-1c)(1.12 g (3.67 mmol) in 2 mL of anhydrous THF) was added dropwise andstirring was continued for 2 hours at room temperature. It was thenquenched with aqueous saturated NH₄Cl and extracted with ethyl acetate.The combined organic extracts were dried over MgSO₄, filtered, andconcentrated. The resulting residue was purified by flash chromatography(SiO₂, dichloromethane/methanol, 0 to 10%)) to afford (I-9a1); m/z 291.0(M+H)⁺.

Intermediate(S)-methyl-3-cyclopentyl-2-(4-dimethylcarbamoyl)-1H-pyrazol-1-yl)-propanoate,(I-9a2), m/z 294.2 (M+H)⁺ was prepared in an analogous manner to thatdescribed for the synthesis of Intermediate (I-9a1) from1H-pyrazole-4-carboxylic acid (Aldrich Chemical Company, Inc.,Milwaukee, Wis.) dimethylamide and Intermediate (I-1c).

Intermediate: 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate(I-10a)

Under argon, diisopropylamine (66.8 g (92.5 mL), 0.66 mol) was dissolvedin THF (1 L) and cooled to −5° C. in an ice/methanol bath. Over 30minutes, n-butyl-lithium (2.34 M, 290 mL, 0.66 mol) was added whilemaintaining the temperature below 1° C. The mixture was stirred at about0° C. to about −5° C. for 15 minutes and cooled to −72° C. with anacetone and dry ice bath. Dihydro-2H-pyran-4(3H)-one (Aldrich ChemicalCompany, Inc., Milwaukee, Wis.) was added slowly over 15 minutes whilemaintaining the temperature at −78° C. for 1 hour.N-phenyl-bis-(trifluoromethyl sulfonimide; Aldrich Chemical Company,Inc., Milwaukee, Wis.) was suspended in THF (500 mL) and added slowly tothe mixture while maintaining a temperature below −60° C. The mixturewas left stirring in the cooling bath, warming to room temperatureovernight. The mixture was concentrated under reduced pressure. Theresidues were slurried in hexane at 50° C. (1 L and 250 mL), the liquorswere concentrated under reduced pressure to afford (I-10a). ¹H NMR(CDCl₃, 300 MHz) δ 5.74 (1H), 4.19 (2H), 3.80 (2H), 2.39 (2H).

Intermediate: (R)-methyl2-(tert-butoxycarbonyl)-3-(3,6-dihydro-2H-pyran-4-yl)propanoate (I-10b)

In rigorously anaerobic conditions, zinc dust (72.7 g, 1.11 mol) wassuspended in anhydrous N,N-dimethylformamide (100 mL), and to thestirred solution, trimethylsilyl chloride (23 mL 0.18 mol) was added(exotherm to 55° C.). The mixture was stirred for 20 minutes, duringwhich time the supernatant became brown in color. The mixture wasallowed to settle, and the supernatant decanted off using vacuum. Theactivated zinc powder was washed with N,N-dimethylformamide (4×50 mL),until the supernatant solvent became colorless.

(R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (OakwoodProducts, West Columbia, S.C.) (85 g, 0.26 mol) was dissolved inN,N-dimethylformamide under argon, added in one portion to the activatedzinc powder and stirred briskly. After approximately 5 minutes, themixture self heated rapidly (21-30° C. over about 15 seconds). Thestirring was stopped and the cooling bath immediately applied, allowingthe exothermic reaction to be ceased at 50° C. As the temperaturesubsided, the cooling bath was removed and the mixture stirred atambient temperature for 20 minutes and allowed to settle. Thesupernatant was syringed into a pre-prepared solution of (I-10a) (60 g,0.26 mol) and PdCl₂(PPh₃)₂ (5.44 g, 7.75 mmol). The metallic solids werewashed with N,N-dimethylformamide (30 mL) and the washings added to thetriflate/catalyst mixture, which was stirred at 50° C. overnight. Thesolution was concentrated under reduced pressure and the crude productslurried in water (500 mL) and 20% ethyl acetate in hexane (500 mL). Themixture was filtered and partitioned, and the aqueous layer re-extractedwith 20% ethyl acetate in hexane (500 mL). The combined organic phaseswere washed with brine (500 mL), dried over MgSO₄, and concentratedunder reduced pressure. The semi-crude product was obtained as a freerunning red-brown oil (81 g), which was purified twice by dry-flashchromatography (SiO₂, ethyl acetate and Hexanes, 2 to 20%) followed bycarbon treatment in 10% ethyl acetate/hexane to afford (I-10b): ¹H NMR(CDCl₃, 300 MHz): δ 5.50 (1H), 4.95 (1H), 4.40 (1H), 4.10 (2H), 3.77(2H), 3.73 (3H), 2.50 (1H), 2.31 (1H), 2.07 (2H), 1.43 (9H).

Intermediate: (R)-methyl2-(tert-butoxycarbonyl)amino-3-(tetrahydro-2H-pyran-4-yl)propanoate(I-10c)

In a stainless steel autoclave, 22.83 g (80.0 mmol) of (I-10b) wasdissolved in methanol (150 mL) to which was added 5% Pd/C (2.3 g) as aslurry in toluene (10 mL). The autoclave was charged to 20 bar withhydrogen and the reaction mixture was stirred for 2 hours at roomtemperature. The mixture was filtered through celite and the filtratesconcentrated under reduced pressure to afford (I-10c). The product wasused in the next step without further purification. ¹H NMR (CDCl₃, 300MHz): δ 4.92 (1H), 4.38 (1H), 3.92 (2H), 3.73 (3H), 3.35 (2H), 1.5-1.8(4H), 1.43 (9H), 1.2-1.4 (2H).

Intermediate: (R)-2-amino-3-(tetrahydro-2H-pyran-4-yl)propanoic acid(I-10d)

First, Intermediate (I-10c) (22.9 g, 80.0 mmol) was suspended in 6Naqueous HCl (200 mL) and heated at 100° C. overnight. The mixture wascooled to room temperature and extracted with 20% ethyl acetate/hexane(100 mL) to remove any unwanted organics. The aqueous phase wasconcentrated under reduced pressure and co-distilled with toluene (2×200mL) to afford the HCl salt of (I-10d), giving a yield of 17.9 g; 108%(off-white powder, presumed damp with water or toluene): ¹H NMR(d₆-DMSO, 300 MHz) δ 8.49 (3H), 3.79 (3H), 3.19 (2H), 2.44 (1H), 1.4-1.9(5H), 1.12 (2H). Secondly, the HCl salt of (I-10d) (11.6 g, 55.3 mmol)and isobutylene oxide (5.33 mL) were suspended in N,N-dimethylformamide(120 mL) in 4 Anton Paar 30 mL microwave vials. The mixtures werereacted at 100° C. for 1 hour and allowed to cool. The mixtures werewashed out of the vials with ethyl acetate (50 mL each), combined andstirred briskly in further ethyl acetate (total volume 500 mL) for 10minutes, during which time a thick cream-coloured suspension formed. Thesolids were filtered off, broken up with a spatula and dried in a vacuumoven at 50° C. overnight to afford Intermediate (I-10d)

Intermediate: (R)-2-hydroxy-3-(tetrahydro-2H-pyran-4-yl)propanoic acid(I-10e)

Intermediate (I-10d) (7.68 g, 44.3 mmol) was dissolved in 1N H₂SO₄ (140mL) and cooled to 0° C. under argon. NaNO₂ (4.6 g, 66.45 mmol) as asolution in water (25 mL) was introduced dropwise under the surface ofthe mixture and the whole stirred overnight. The mixture was extractedwith ethyl acetate (100 mL). The aqueous phase was extracted withfurther ethyl acetate (5×100 mL). The aqueous phase was cooled to 0° C.under argon and re-dosed with concentrated H₂SO₄ (3.5 mL) and NaNO₂ (4.6g, 66.45 mmol) as a solution in water (25 mL) and stirred overnight. Themixture was extracted with ethyl acetate (6×100 mL), re-dosed as above,stirred overnight and finally extracted a third time with ethyl acetate(6×100 mL). All 1800 mL of organics were combined and stripped to affordcompound (I-10e) with a yield of 7.0 g (91%) as an orange oil. ¹H NMR(CD₃OD, 300 MHz): δ 4.20 (1H), 3.92 (2H), 3.39 (2H), 1.7 (2H), 1.6 (2H),1.27 (2H).

Intermediate: (R)-methyl2-hydroxy-3-(tetrahydro-2H-pyran-4-yl)propanoate (I-10f)

Intermediate (I-10e) (9.0 g, 51 mmol) was dissolved in methanol (100 mL)and stirred. HCl was sparged in to the mixture for 15 minutes(exothermic 20° C. to 65° C.) and the whole was refluxed for 7 hours andallowed to cool. The mixture was stripped to approximately ⅓ volume,diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL).The organics were stripped and the crude product purified by dry-flashchromatography (SiO₂, ethyl acetate and hexanes, 10 to 20%)) to 3.8 g of(I-10f). The aqueous phase was re-extracted with ethyl acetate (2×200mL), stripped, and re-purified to a further 1.2 g of (I-10f): ¹H NMR(CDCl₃, 300 MHz): δ 4.24 (1H), 3.95 (2H), 3.78 (3H), 3.39 (2H), 2.73(1H), 1.83 (1H), 1.52-1.75 (4H), 1.22-1.42 (1H).

Intermediate: (R)-methyl3-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethylsulfonyloxy)-propanoate(I-10g)

Intermediate (I-10f), (1.21 g, 6.43 mmol) was dissolved in anhydrousdichloromethane (60 mL) under nitrogen. The mixture was stirred in anice bath, and lutidine (1.6 mL) was added. Triflic anhydride (1.95 mL,11.6 mmol) was added dropwise, and the reaction was stirred for 60minutes then was diluted with methyl tert-butyl ether, and washed 3times with 3:1 brine/1 N HCl. The organic layer was dried over MgSO₄,filtered, evaporated, and dried under high vacuum to afford (I-10g),which was utilized in the following reaction without furtherpurification.

Intermediate: (S)-methyl3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate(I-10h)

4-(trifluoromethyl)-1H-imidazole (Flourine Chemicals, Shanghai, China)(291 mg) was stirred in 20 mL anhydrous THF at room temperature undernitrogen. A lithium bis(trimethylsilyl)amide solution (1.96 mL, 1.0 M inTHF) was added. After 50 minutes, a solution of intermediate (I-10g)(685 mg) in 10 mL anhydrous THF was added. The reaction was stirred for2 hours. The reaction was quenched with saturated ammonium chloride anddiluted with brine and ethyl acetate. The aqueous layer was extracted,dried, filtered, and then concentrated. The resulting residue waspurified (Combi-flash, Redi-sep 40 g, 30% ethyl acetate/heptane gradientto 100% ethyl acetate/heptane) to afford (I-10h): m/z 307.4 (M+H)⁺.

Intermediate: 5-(methylsulfonyl)-1H-tetrazole (I-11a)

To a stirred solution of 5-(methylthio)-1H-tetrazole (300 mg; AldrichChemical Company, Inc., Milwaukee, Wis.) in THF (15 mL) and water (15mL) was added potassium peroxomonosulfate (Oxone®, DuPont SpecialtyChemicals, Deepwater, N.J., USA) (3.18 g). After stirring at roomtemperature for five days, the reaction mixture was filtered and thefiltercake was washed with THF. The filtrate was concentrated underreduced pressure. Crude NMR showed this to be a mixture of desiredproduct and starting material, so the mixture was taken up in methanoland treated with potassium peroxomonosulfate (Oxone®, DuPont SpecialtyChemicals, Deepwater, N.J., USA). After stirring at room temperature forfive days, the reaction mixture was filtered and the filtercake waswashed with methanol. The filtrate was concentrated under reducedpressure to afford 0.400 g of impure (I-11a)as a solid which was used inthe next step without purification; m/z 146.9 (M−H)⁻.

Intermediate: (S)-methyl3-cyclopentyl-2-(5-(methylsulfonyl)-2H-tetrazol-2-yl)propanoate (I-11b)

To a stirred solution of 200 mg of (I-11a) in anhydrous THF (10 mL)under nitrogen was added lithium bis(trimethylsilyl)amide (0.276 mL, 1 Min THF). After stirring for 40 minutes, a solution of Intermediate(I-1c) (414 mg) in anhydrous THF (2 mL) was added dropwise. After 2hours, the reaction was quenched with aqueous saturated NH₄Cl andextracted with ethyl acetate twice. The combined organics were driedover MgSO₄ and purified by flash chromatography (10 g snap Biotage,0-10% methanol in dichloromethane) to give 0.180 g of (I-11b)as an oil;m/z 303.1 (M+H)⁺.

Intermediate: (R)-2-amino-3-(tetrahydrofuran-2-yl)propanoic acid (I-12a)

In a 400 mL beaker, D-2-furyl alanine (8.16 g, 52.6 mmol; Chem-ImpexInternational, Inc., Wood Dale, Ill.) was slurried in water (200 mL)with 10% Pd/C (0.85 g). The beaker was placed in the bottom of a 2Lstainless steel autoclave, charged to 20 bar (290 psi) with hydrogen andstirred for 5 hours at RT. TLC (1:1:1:1:1toluene/acetone/butan-1-ol/water/acetic acid) showed some startingmaterial remained. The reaction was re-charged with hydrogen to 20 barand stirred overnight at RT, after which time TLC showed that startingmaterial was no longer present. The mixture was filtered through a padof celite (pad washed with 2×200 ml water), and the combined filtratesstripped to afford (I-12a) as a brown solid that was a mixture ofdiastereomers (8.4 g, 52.8 mmol, 100%): ¹H NMR (400 MHz, TFA-d): δ 84.60(2H), 4.12 (2H), 2.58 (1H), 2.40 (2H), 2.1-2.35 (4H), 1.89 (2H).

Intermediate: (R)-2-hydroxy-3-(tetrahydrofuran-2-yl)propanoic acid(I-12b)

Intermediate (I-12a) (8.4 g, 52. 8 mmol) was dissolved in 1N H₂SO₄ (160mL) and cooled in an ice/brine bath to 0° C. NaNO₂ (5.46 g, 79.2 mmol)as a solution in water (20 mL) was trickled in under the surface of thesolution, and the mixture stirred overnight, gradually warming to RT.The mixture was extracted with ethyl acetate (6×100 mL), TLC (TABWA)showed product in each fraction, tailing off towards the end, TLC of theaqueous phase showed starting material remained. The aqueous phase wascooled to 3° C. and carefully re-dosed with conc. H₂SO₄ (4.5 mL),followed by further NaNO₂ (5.46 g, 79.2 mmol) in water (20 mL) at −2° C.The mixture was warmed to room temperature overnight, and the followingmorning extracted and re-dosed as above, three more times. The finalextracts showed no significant amount of product, and no obviousstarting material in the aqueous phase. The combined organics werestripped to afford (I-12b) as an orange oil that was a mixture ofdiastereomers (8.34 g, 52.0 mmol, 98%), known to be slightly impure byNMR: ¹H NMR (400 MHz, CD₃OD): δ 4.22 (1H), 4.05 (1H), 3.81 (1H), 3.69(1H), 1.82-2.10 (5H), 1.55 (1H).

Intermediate: (R)-methyl 2-hydroxy-3-(tetrahydrofuran-2-yl)propanoate(I-12c)

Intermediate (I-12b) (4.23 g, 26.4 mmol) was dissolved in HPLC grademethanol (100 mL) and to this Amberlyst-15 (4.23 g) was added in oneportion, and the mixture stirred for 72 hours. An aliquot was filteredand stripped, and the ¹H NMR showed only product present. The mixturewas combined for workup with two other runs (1 g, 6.2 mmol of I-12b and1.99 g, 12.4 mmol of I-12b). The combined mixtures were filtered througha pad of Celite, and the pad washed with ethyl acetate (2×100 mL), thecombined filtrates were stripped to give the crude product as a yellowoil (6.2 g, 35.6 mmol, 79%). The crude product was purified by columnchromatography (ethyl acetate/hexane 1:1), to afford (I-12c) as a paleyellow oil that was a mixture of diastereomers (3.9 g, 22.4 mmol, 43%):¹H NMR (400 MHz, CDCl₃): δ 4.33 (1H), 3.73 (1H), 3.73 (2H), 3.72 (3H),1.8-2.1 (5H), 1.51 (1H).

Intermediate: (2R)-methyl3-(tetrahydrofuran-2-yl)-2-(trifluoromethylsulfonyloxy)propanoate(I-12d)

Intermediate (I-12c) (1.57 g, 9 mmol) was added to a nitrogen purgedflask and dissolved in 18 mL anhydrous dichloromethane. The temperaturewas brought to 0° C. and 2,6-lutidine (1.8 mL, 16 mmol) was addedfollowed by dropwise triflic anhydride (2.48 mL, 14.8 mmol). This yellowsolution was stirred at 0° C. for 45 min before adding ether and washingwith a mixture of water and 1N HCl (pH=1). The organic layer was washedwith brine and then dried over MgSO₄ and concentrated to afford 3.40 gof (I-12d) as a yellow oil that was a mixture of diastereomers. This wascarried on without characterization.

Intermediate: (S)-methyl3-(tetrahydrofuran-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate(I-12e)

4-(Trifluoromethyl)-1H-imidazole (397 mg, 2.9 mmol) was stirred inanhydrous THF (4 mL) under nitrogen and lithium hexamethyldisilazide(2.90 mL, 1 M in THF, 2.9 mmol) was added. This was stirred at RT as asolution for 90 min before adding a solution of intermediate (I-12d)(900 mg, 2.9 mmol) in 3 mL anhydrous THF dropwise. The reaction wasstirred as a mixture at RT for 3 hr. The reaction was quenched withsaturated NH₄Cl solution, and extracted with ethyl acetate twice. Thecombined organics were dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was chromatographed (Isco, 12 gramRediSep Column eluting with 30-50% ethyl acetate/Heptane) to afford 370mg (43%) of (I-12e) as a yellow solid that was a mixture ofdiastereomers; m/z 293.1 (M+H)⁺.

Intermediate: (R)-methyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate (I-13a)

In a 50 mL round bottomed flask, methyl-2R-glycidate (2.5 g, 24.5 mmol)and pyrazole (4.17 g, 61.2 mmol) were dissolved in industrial methylatedspirits (25 mL) and refluxed for 5 hours. A 0.2 mL sample was withdrawn,stripped and tested by ¹H NMR, showing all of the methyl-2R-glycidatewas consumed. The reaction was allowed to cool, stripped and codistilledwith methanol (20 mL). The crude material, a yellow oil, (6.67 g) wascombined with 130 mg of crude material from a previous experiment, andpurified by column chromatography (20%-50% ethyl acetate/hexane). Twofractions were collected and analysed by NMR, the primary spot materialcontained approximately 5% pyrazole, and the secondary spot approx 27%.The two fractions were re-purified separately to afford (I-13a) as ayellow oil. (2.6 g, 15.2 mmol, 62%): ¹H NMR (400 MHz, CDCl₃): δ 7.50(1H), 7.42 (1H), 6.24 (1H), 4.55 (1H), 4.47 (2H), 3.77 (3H).

Intermediate: (R)-methyl3-(1H-pyrazol-1-yl)-2-(trifluoromethylsulfonyloxy)propanoate (I-13b)

Intermediate (I-13a) (800 mg, 4.7 mmol) was weighed into a flask anddissolved in dry dichloromethane (60 mL) under nitrogen. The mixture wasstirred in an ice bath, and 2,6-lutidine (1.2 mL, 10 mmol) was added.Trifluoromethane sulfonic acid anhydride (1.4 mL, 8.5 mmol) was addeddropwise, and the reaction was stirred for 60 minutes, diluted withmethyl tert-butyl ether (50 mL), and washed three times with 3:1brine:HCl. The organic layer was dried over sodium sulfate, filtered,concentrated under reduced pressure, and dried under high vacuum toaffor (I-13b) as a light brown oil (1.42 g, 4.7 mmol, 100%). Thecompound was used crude in the next step; ¹H NMR (400 MHz, CDCl₃) δ 7.61(1H), 7.47 (1H), 6.27-6.37 (1H), 5.50-5.54 (1H), 4.56-4.85 (2H), 3.88(3H).

Intermediate: (S)-methyl3-(1H-pyrazol-1-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate(I-13c)

4-(Trifluoromethyl)-1H-imidazole (640 mg, 4.7 mmol) was stirred in dryTHF (30 mL) at room temperature under nitrogen. Lithiumhexamethyldisilazide (1M in THF, 4.2 mL, 4.2 mmol) was added. After 45minutes, a solution of Intermediate (I-13b) (1.42 g, 4.7 mmol) in dryTHF (20 mL) was added. The reaction was stirred for 12 hours. Thereaction was quenched with saturated ammonium chloride and diluted withbrine and ethyl acetate. Enough water was added to dissolve theprecipitated salts. The aqueous layer was extracted with ethyl acetate,and the combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography, eluting with 100% heptane gradient to 80% ethylacetate/heptane. The appropriate fractions were combined, evaporated,and dried under high vacuum to afford (I-13c) as a yellow oil (689 mg,2.39 mmol, 57%). m/z 289.2 (M+H)⁺.

Intermediate:(S)-3-cyclopentyl-N-(5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide(I-14a)

To a solution of (I-8b) (167 mg, 0.605 mmol) in 3 mL anhydrousdichloromethane at 0° C. was added dropwise oxalyl chloride (0.129 mL,1.45 mmol) followed by 2 drops of N,N-dimethylformamide. This wasstirred at 0° C. for 5 minutes and then at room temperature for 60minutes before concentrating under reduced pressure. 1,2-Dichloroethanewas added and concentrated to ensure all oxalyl chloride was removed.This residue was then dissolved in 3 mL anhydrous dichloromethane andbrought to 0° C. In a separate vial(S)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-amine (118 mg, 0.605mmol), prepared as in Chen, et al. US 2004/0147748, was combined withdichloromethane (2 mL) and pyridine (0.147 mL, 1.82 mmol). The aminesolution was then added to the acid chloride solution. The ice bath wasallowed to melt and the reaction was stirred for 15 h. The reactionmixture was diluted with dichloromethane (50 mL) and 1N HCl (5 mL), thelayers were separated, and the aqueous layer was extracted withdichloromethane. The combined organics were dried over MgSO₄ andpurified by silica gel chromatography (12g-Snap Biotage, heptane/ethylacetate) to give three fractions of impure desired material. These werecombined, diluted with dichloromethane, washed with saturated aqueoussodium bicarbonate and dried over MgSO₄. This was filtered andconcentrated in vacuo to afford 76 mg of (I-14a) as an oil; m/z 454.1(M+H)⁺.

Intermediate: 3-(trifluoromethyl)-1H-1,2,4-triazole (I-15a)

Hydrazine monohydrate (4.8 g, 96 mmol) was dissolved in industrialmethylated spirits (160 mL) and cooled to 0° C. before ethyltrifluoroacetate (14 g, 100 mmol; Aldrich Chemical Company, Inc.,Milwaukee, Wis.) was added dropwise. The resulting reaction mixture wasthen warmed to ambient temperature and stirred for 1 hour. After thistime, the solvent was removed under vacuum and the residue re-dissolvedin industrial methylated spirits (100 mL). Formamidine acetate (9.9 g,95 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) was then addedand the reaction mixture heated to 80° C. for 2.5 hours. The reactionwas then cooled to ambient temperature and the solvent removed undervacuum. To the residue was then added NaHCO₃ (aq.) (100 mL), and theproduct was extracted with ethyl acetate (2×100 mL), dried over MgSO₄,filtered and the solvent removed under vacuum. The crude product wasthen purified by flash chromatography (1:3 hexane/ethyl acetate), giving˜10 g of a pale peach oil, which crystallised on standing overnight. Thecrystals were then filtered, washed with hexane and dried overnight inan oven to afford (I-15a) as colorless crystals (8.73 g, 66% yield): ¹HNMR (400 MHz, DMSO-d₆): δ 8.81 (1H).

Intermediate: (S)-methyl3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanoate(I-15b)

Intermediate (I-15a) (248 mg, 1.8 mmol) was dissolved in dry THF (20 mL)under argon and lithium hexamethyldisilazide (1 M in THF, 1.62 mL, 1.62mmol) was added. The reaction mixture was then stirred at ambienttemperature for 30 minutes before Intermediate (I-1c) (550 mg, 1.8 mmol)was added as a solution in THF (20 mL), and the resulting reactionmixture stirred at ambient temperature for 16 hours. After this time,the reaction was quenched by the addition of NH₄Cl (aq.) (10 mL) at 0°C. and the product was extracted with ethyl acetate (2×40 mL), driedover MgSO₄, filtered and the solvent removed under vacuum. The crudeproduct was then purified by flash chromatography (2:1 hexane/ethylacetate) to afford (I-15b) as a colorless oil (198 mg, 42% yield): ¹HNMR (400 MHz, CDCl₃): δ 8.34 (1H), 5.10 (1H), 3.78 (3H), 2.28-2.16 (2H),1.83-1.76 (1H), 1.74-1.47 (6H), 1.21-1.04 (2H).

Intermediate:(S)-3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanoicacid (I-15c)

6N HCl (10 mL) was added to Intermediate (I-15b) (380 mg, 1.30 mmol) andthe mixture was warmed to 95° C. for 16 hours and then allowed to cool.Solid potassium carbonate was added to bring the pH to about 4. Themixture was diluted with water and ethyl acetate. The aqueous layer wasextracted once with ethyl acetate. The combined organics were washedwith brine, dried over sodium sulfate, filtered, evaporated, and driedunder high vacuum to afford (I-15c); m/z 277.9 (M+H)⁺.

Intermediate: (R)-methyl3-cyclohexyl-2-(trifluoromethylsulfonyloxy)propanoate (I-16a)

To a 100 mL round bottom flask containing D-cyclohexylalaninehydrochloride (10 g, 48 mmol; Chem-Impex International, Inc., Wood Dale,Ill.) was added 2N H₂SO₄ (50 mL), and the stirred solution was cooled to0° C. To this solution was added NaNO₂ (5 g, 72.2 mmol) as a solution inH₂O (5 mL) dropwise over 5 min. The reaction mixture was stirred for 3hr at 0° C. and then the bath was allowed to melt and come to roomtemperature overnight. The solution was transferred to a separatoryfunnel and extracted with methyl tert-butylether twice. The combinedorganics were dried over MgSO₄and concentrated to afford 6 g of amixture of product and starting material as a pale oil. The aqueouslayer was placed in the original round bottom flask and another 4 mLconc. H₂SO₄ was added. After cooling to 0° C., a solution of NaNO₂ (2 g)in H₂O (0.5 mL) was added. The reaction was stirred at 0° C. for severalhours before being allowed to come slowly to room temperature overnightand stirred at room temp for 16 hours. The 6 g mixture was dissolved in2N H₂SO₄ (50 mL), and the stirred solution was cooled to 0° C. To thissolution was added NaNO₂ (2.5 g, 36.1 mmol) as a solution in H₂O (5 mL)dropwise over 5 min. The reaction mixture was stirred for 3 hr at 0° C.and then the bath was allowed to melt and come to room temperatureovernight. Both reactions were combined and transferred to a separatoryfunnel and then extracted with methyl tert-butylether twice. Thecombined organics were dried over MgSO₄ and concentrated to afford(I-16a) (4.8 g) as pale oil; m/z 171.1 (M−H)⁻.

Intermediate: (R)-methyl 3-cyclohexyl-2-hydroxypropanoate (I-16b)

To a solution of intermediate (I-16a) (6.3 g, 36.58 mmol) in anhydrousmethanol (50 mL) was added thionyl chloride (4. mL, 54.9 mmol) dropwiseand then the reaction was refluxed for 60 minutes. It was then cooleddown and concentrated in vacuo. The residue was partitioned betweenethyl acetate and sat. NaHCO₃. The aqueous layer was extracted withethyl acetate and the combined organics dried over MgSO₄, filtered, andevaporated to give a crude oil. The crude product was purified withsilica gel chromatography (Biotage 40+M, eluting with 0-30% (3 CV), 30%(3 CV), 30-100% (1 CV), 100% (2 CV) ethyl acetate/heptane) to afford(I-16b) (2.4 g) as a colorless oil: ¹H NMR (400 MHz, CDCl₃): δ 4.12-4.34(1H), 3.77 (3H), 2.45-2.72 (1H), 1.80 (1H), 1.42-1.75 (7H), 1.04-1.35(3H), 0.71-1.01 (2H).

Intermediate: (R)-methyl3-cyclohexyl-2-(trifluoromethylsulfonyloxy)propanoate (I-16c)

2,6-Lutidine (0.354 mL, 3.04 mmol) was added to a flask containingintermediate (I-16b) (298 mg, 1.6 mmol) in anhydrous dichloromethane (7mL) purged with nitrogen at 0° C. To this was addedbis(trifluoromethanesulfonic)anhydride (0.469 mL, 2.72 mmol) and stirredfor 40 min. The solution was observed to be light yellow. The reactionmixture was concentrated and taken up in diethyl ether. This was washedwith brine (3×), and aq. 1N HCl (3×). The organic layer was dried oversodium sulfate, filtered, and concentrated afford (I-16c) (509 mg); m/z319.0 (M+H)⁺.

Intermediate: (S)-methyl3-cyclohexyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate (I-16d)

4-(Trifluoromethyl)-1H-imidazole (204 mg, 1.50 mmol) was taken up inanhydrous THF and purged with nitrogen. To this added lithiumhexamethyldisilazide (1.50 mL, 1.15 mmol, 1 M in THF) and the reactionwas stirred as a solution for 40 min at room temperature. After 40 min,intermediate (I-16c) (478 mg, 1.28 mmol) in 2 mL of anhydrous THF wasadded dropwise. This was stirred at room temperature for 2 hours atwhich point the reaction had turned dark yellow. After 2 hours, thereaction mixture was quenched with aqueous saturated NH₄Cl. Ethylacetate was added and the material transferred to a separatory funnel.The organic layer was washed with aq. 1M HCl (3×), water (3×), aqueoussodium bicarbonate and brine (2×). The organic layer was dried oversodium sulfate, filtered, and concentrated to a crude residue.Purification of the crude product was performed using a combiflash/iscocompanion system (SiO₂, with a gradient of 0-60% ethyl acetate/heptane)to afford (I-16d) as a yellow oil; m/z 305.0 (M+H)⁺.

Intermediate: (S)-benzyl6-(3-cyclohexyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate(I-16e)

Intermediate (I-28a) (272 mg, 1.19 mmol) was taken up in 4 mL oftoluene. The amine was observed to be insoluble. Dimethylaluminumchloride (1.19 mL, 1.19 mmol) was added to this mixture. The solidsdissolved and the solution was observed to be bright yellow/green.Within one minute, this solution was added to a 50° C. solution ofintermediate (I-16d) (250 mg, 0.822 mmol) in 3 mL of toluene. Thisyellow solution was stirred at 50° C. for 2 hours then 0.3 eq more ofdimethylaluminum chloride was added and stirred for another hour. Theheat was discontinued and aqueous saturated Rochelle's salt (15 mL) wasadded and stirred for 0.5 hrs. 15 mL of ethyl acetate was used totransfer to a separatory funnel. The organic layer was washed with water(3×) and brine (2×). The organic layer was dried over sodium sulfate,filtered, and concentrated to a crude residue. Purification of the crudeproduct was performed using a combiflash/isco companion system with agradient of 0-50% ethyl acetate/heptane to afford (I-16e) as a clearfoam; m/z 501.0 (M+H)⁺.

Intermediate: (S)-methyl3-cyclopentyl-2-(2-methyl-4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate(I-17a)

To a stirred solution of 2-methyl-4-(trifluoromethyl)-1H-imidazole(Chireach USA LLC, San Diego, Calif.) (197 mg, 1.3 mmol) in anhydrousTHF (8 mL) under N₂ was added a solution of lithium hexamethyldisilazide(1.24 mL, 1 M in hexanes, 1.24 mmol). After stirring for 45 minutes atroom temperature, a solution of Intermediate (I-1c) (400 mg, 1.32 mmol)in 8 mL of anhydrous THF was added dropwise and stirring was continuedfor 4 hours at room temperature. It was then quenched with aqueoussaturated NH₄Cl and extracted with ethyl acetate. The combined organicextracts were dried over MgSO₄, filtered, and concentrated. Theresulting residue was purified by flash chromatography (SiO₂,heptane/ethyl acetate, 0 to 50%) to afford (I-17a) in 47% yield; m/z305.4 (M+H)⁺.

Intermediate: (S)-benzyl6-(3-cyclopentyl-2-(2-methyl-4-(trifluoromethyl)-1H-imidazol-1-yl)propenamido)nicotinate(I-17b)

Intermediate (I-28a) was taken up in 3 mL of toluene. The amine wasobserved to be insoluble. Dimethylaluminum chloride (0.44 mL, 1.0M inhexanes, 1.19 mmol) was added to this mixture. The solids dissolved andthe solution was observed to be bright yellow/green. Within one minute,this solution was added to a 50° C. solution of intermediate (I-17a) in2 mL of toluene. This yellow solution was stirred at 50° C. for 2 hoursthen another 0.3 eq of 1.0 M dimethylaluminum chloride was added andstirred for another hour. The reaction was cooled to room temperatureover 1 hour and then saturated aqueous Rochelle's salt (15 mL) was addedand stirred for 0.5 h. 15 mL of ethyl acetate was used to transfer thematerial to a separatory funnel. The organic layer was washedsequentially with water (3×) and brine (2×). The organic layer was driedover sodium sulfate, filtered and concentrated under reduced pressure.The crude residue was purified by silica gel chromatography (20-80%ethyl acetate/heptane) to afford (I-17b); m/z 501.4 (M+H)⁺.

Intermediate: (S)-methyl3-cyclopentyl-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanoate(I-18a)

To a stirred solution of 4-methyl-3-(trifluoromethyl)-1H-pyrazole (RyanScientific, Inc., Mt. Pleasant, S.C.) (197 mg, 1.3 mmol) in anhydrousTHF (8 mL) under nitrogen was added a solution of lithiumhexamethyldisilazide (1.24 mL, 1 M in hexanes, 1.24 mmol). Afterstirring for 45 minutes at room temperature, a solution of Intermediate(I-1c) (400 mg, 1.32 mmol) in 8 mL of anhydrous THF) was added dropwiseand stirring was continued for 4 hours at room temperature. It was thenquenched with aqueous saturated NH₄Cl and extracted with ethyl acetate.The combined organic extracts were dried over MgSO₄, filtered, andconcentrated. The resulting residue was purified by flash chromatography(SiO₂, heptane/ethyl acetate, 0 to 50%) to afford (I-18a) in 70% yield;m/z 305.4 (M+H)⁺.

Intermediate:(S)-3-cyclopentyl-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanoicacid (I-18b)

6N HCl (2 mL) was added to Intermediate (I-18a) (89 mg, 0.29 mmol) andthe mixture was warmed to 95° C. for 16 hours and then allowed to cool.Solid potassium carbonate was added to bring the pH to about 3. Aprecipitate crashed out. Ethyl acetate was added, and the mixture wasstirred until everything was dissolved. The aqueous layer was extractedonce with ethyl acetate. The combined organics were washed with brine,dried over sodium sulfate, filtered, evaporated, and dried under highvacuum to afford impure (I-18b) with some starting material present; m/z290.9 (M+H)⁺.

Intermediate:(2S)-3-cyclopentyl-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propanamide(I-19a)

Intermediate (I-8b) (150 mg, 0.54 mmol) in dichloromethane undernitrogen was treated with oxalyl chloride (0.1 mL, 1.1 mmol) and onedrop of N,N-dimethylformamide. The reaction was stirred for 1 hr andthen concentrated. The residue, dissolved in dichloromethane, wastreated with ammonia in dioxane (0.5M, 3 mL). The resulting mixture wascapped and stirred overnight. The reaction mixture was concentrated toafford (I-19a) (80 mg, 54%); m/z 276.1 (M+H)⁺.

Intermediate: 3-methyl-4-(trifluoromethyl)-1H-pyrazole (I-20a)

A solution of 4,4,4-trifluorobutan-2-one (2.0 g, 16 mmol; Alfa Aesar,Ward Hill, Mass.) and 1,1-dimethoxy-N,N-dimethylmethanamine (4.2 mL, 32mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in toluene (13mL) was stirred at reflux for 4 h. The reaction was cooled and themixture was concentrated in vacuo. The crude residue was taken up inethanol (13 mL) and hydrazine (3.7 mL) was added. The mixture wasstirred at room temperature overnight before concentrating in vacuo. Theresidue was redissolved in ethyl acetate and washed with water. Theaqueous layer was reextracted with ethyl acetate three times. Thecombined organic layer was dried over sodium sulfate, filtered, andconcentrated to afford impure (I-20a) as a red oil (1.28 g). This wascarried on without further purification. ¹H NMR (400 MHz, CDCl₃): δ 7.73(1H), 2.42 (3H).

Intermediates: (S)-methyl3-cyclopentyl-2-(3-methyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)propanoate(I-20b), (S)-methyl3-cyclopentyl-2-(5-methyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)propanoate(I-20c)

Intermediate (I-20a) (150.1 mg, 1.00 mmol) was stirred in 5 mL of dryTHF at room temperature under nitrogen. Lithium hexamethyldisilazidesolution (1.0M in THF, 0.91 mL, 0.909 mmol) was added dropwise. After 50minutes, a solution of intermediate (I-1c) (304 mg, 1.00 mmol) in 1 mLof dry THF was added. The reaction was stirred for 3 hours. The reactionwas quenched with saturated aqueous ammonium chloride and extracted withethyl acetate three times. The combined organic layer was concentratedand purified by silica gel chromatography (ISCO 12 g, ethylacetate/heptane 30-100%) to afford a mixture of (I-20b) and (I-20c) as ayellow oil (153 mg); m/z 304.9 (M+H)⁺.

Intermediate:(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinoylchloride (I-21a)

Thionyl chloride (225 mg, 1.89 mmol) was added to a solution of thecompound of Example 48 (150 mg, 0.387 mmol) in dichloromethane (1.5 mL)and the reaction stirred at room temperature for 1 hour. LCMS of analiquot in methanol showed ˜67% methyl ester. To the reaction mixturewas added another 25 uL of thionyl chloride and this was stirred at roomtemp for another 30 minutes. Solvents were evaporated to afford 157 mg(100%) of (I-21a) as a grayish-white solid. LCMS in methanol to generatethe methyl ester gave m/z 395.9 (M+H)⁺.

Intermediate: benzyl 5-aminopyrazine-2-carboxylate (I-22a)

5-aminopyrazine-2-carboxylic acid (493 mg, 3.54 mmol; Ark Pharm, Inc.,Libertyville, Ill.) was stirred in dry N,N-dimethylformamide (3.0 mL) atroom temperature under nitrogen. Solid potassium carbonate (742 mg, 5.37mmol) was added, followed by benzyl bromide (0.43 mL, 3.6 mmol). Themixture was stirred for 22 hours and then diluted with ethyl acetate andwater. The layers were separated, and the aqueous layer was extractedwith ethyl acetate. The combined organics were washed with brine, driedover sodium sulfate, filtered, and evaporated. The residue was purifiedby silica chromatography using a 40 g pre-packed column, eluting withethyl acetate. The product fractions were combined, evaporated, anddried under high vacuum to afford (I-22a) (161.2 mg, 0.70 mmol, 20%):m/z 229.9 (M+H)⁺.

Intermediate:(S)-3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanoic acid(I-23a)

6N HCl (4 mL) was added to Intermediate (I-4a2) (189 mg, 0.629 mmol) andthe mixture was warmed to 95° C. for 16 hours and then allowed to coolto room temperature. Solid potassium carbonate was added to bring the pHto about 3. Ethyl acetate was added, and the mixture was stirred untileverything was dissolved. The aqueous layer was extracted once withethyl acetate. The combined organics were washed with brine, dried oversodium sulfate, filtered, evaporated, and dried under high vacuum toafford (I-23a); m/z 286.8 (M+H)⁺.

Intermediate:(S)-3-cyclopentyl-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanoic acid(I-24a)

6N HCl (1 mL) was added to Intermediate (I-7a3) (50 mg, 0.17 mmol) andthe mixture was warmed to 95° C. for 16 hours and then allowed to coolto room temperature. Solid potassium carbonate was added to bring the pHto about 3. Ethyl acetate was added, and the mixture was stirred untileverything was dissolved. The aqueous layer was extracted once withethyl acetate. The combined organics were washed with brine, dried oversodium sulfate, filtered, evaporated, and dried under high vacuum toafford (I-24a); m/z 284.9 (M−H)⁻.

Intermediate: diethyl 6-aminopyridin-3-ylphosphonate (I-25a)

A mixture of 2-amino-5-bromopyridine (5 g, 0.029 mol; Aldrich ChemicalCompany, Inc., Milwaukee, Wis.), diethyl phosphate (5.02 g, 0.036 mol),triethylamine (4.4 g, 0.043 mol), Pd(OAc)₂ (0.78 g, 3.4 mmol),triphenylphosphine (2.28 g, 8.7 mmol) in ethanol (100 mL) was refluxedfor 14 hours under nitrogen. TLC (Petroleum ether/ethyl acetate=1:1)indicated that the reaction was complete. The resulting mixture wasfiltered, and the filtrate was concentrated in vacuo, the residue waspurified by prep. HPLC to afford (I-25a) (4.3 g, 64.4%) as a whitesolid; m/z 231.3 (M+H)⁺.

Intermediate: Imidodicarbonic acid, N-(5-methyl-2-pyridinyl)-,C,C′-bis(1,1-dimethylethyl)ester (I-26a)

To a solution of compound 2-amino-5-methylpyridine (10.0 g, 0.092 mol)in dichloromethane (200 mL) was added diisopropylethylamine (23.86 g,0.185 mol) dropwise at 0° C. After the addition, a solution of (Boc)₂O(50.4 g, 0.231 mol) in dichloromethane (50 mL) was added to the mixture,followed N,N-dimethylaminopyridine (11.3 g, 0.092 mol), the resultingmixture was stirred at room temperature for 12 hours. TLC (petroleumether/ethyl acetate=1:1) indicated that the reaction was complete. Themixture was washed with aq. NH₄Cl (50 mL), the residue was extractedwith dichloromethane (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and evaporated in vacuo, the residue waspurified by chromatography on silica to afford (I-26a) (11.4 g, 40%) asa white solid.

Intermediate: Imidodicarbonic acid, N-[5-(bromomethyl)-2-pyridinyl]-,C,C′-bis(1,1-dimethylethyl)ester (I-26b)

A mixture of intermediate (I-26a) (5 g, 0.016 mol), N-bromosuccinimide(2.9 g, 0.016 mol), benzoyl peroxide (0.37 g, 0.0016 mol) in carbontetrachloride (70 mL) was refluxed for 12 hours. TLC (petroleumether/ethyl acetate=5:1) indicated that the reaction was not complete.The reaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by chromatography on silica to afford(I-26b) (3.1 g, 49.5%) as a white solid.

Intermediate: Imidodicarbonic acid,N-[5-[(diethoxyphosphinyl)methyl]-2-pyridinyl]-,C,C′-bis(1,1-dimethylethyl)ester (I-26c)

A mixture of intermediate (I-26b) (4.0 g, 0.01 mol), triethyl phosphite(5.2 g, 31.2 mmol) in THF (100 mL) was refluxed for 72 hours. TLC(petroleum ether/ethyl acetate=1:1) indicated that the reaction was notcomplete. The reaction mixture was concentrated in vacuo, and theresidue was purified by chromatography on silica to afford (I-26c) (4.4g, 95.6%) as an oil.

Intermediate: diethyl(6-aminopyridin-3-yl)methylphosphonate (I-26d)

A mixture of intermediate (I-26c) (4.7 g, 0.011 mmol) andtrifluoroacetic acid (14 mL) in dichloromethane (60 mL) was stirred atroom temperature for 2 hours. TLC (petroleum ether/ethyl acetate=0:1)indicated that the reaction was complete. The reaction mixture waswashed with aq. NaHCO₃ (100 mL). The mixture was extracted withdichloromethane (20 mL×3). The combined organic phases were concentratedto afford (I-26d) (1.8 g, 69.7%) as a white solid; ¹H NMR (400 MHz,CDCl₃): δ 7.87 (1H), 7.37 (1H), 6.40 (1H), 4.33 (2H), 3.98 (4H), 2.90(2H), 1.20 (6H).

Intermediate: 3-nitro-1H-pyrazole (I-27a)

A solution of 1-nitro-1H-pyrazole (4.23 gm, 37.4 mmol; Oakwood Products,Inc., West Columbia, S.C.) in benzonitrile (42 mL) was heated to refluxfor 2 hours. After cooling to 45° C., the reaction mixture, which wasstarting to precipitate, was poured into 175 mL hexanes. A white solidprecipitated. This was collected by vacuum filtration, rinsed repeatedlywith hexane and dried under high vacuum to afford 3.85 grams (91%) of(I-27a) as a white solid; ¹H NMR (400 MHz, DMSO-d₆) δ 13.90 (1H), 8.01(1H), 7.01 (1H).

Intermediate: 3-nitro-1H-pyrazole (I-27b)

Intermediate (I-27a) (830 mg, 7.0 mmol) was dissolved in anhydrousN,N-dimethylformamide (20 mL) in a heavy walled reaction tube. Potassiumcarbonate (1.408 g, 10.19 mmol) and dimethyl oxirane (1.016 g, 14.09mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) were added andthe tube was sealed with a teflon screw cap and heated to 100° C. withstirring for 1 hour. After cooling to room temperature, the reaction wasdiluted with water (40 mL) and extracted with ethyl acetate (3×30 mL).The combined organic layers were dried over Na₂SO₄, filtered, andevaporated. The crude material was purified by silica gel flashchromatograpy (50-60% ethyl acetate/heptane over 40 minutes) to afford985 mg (76%) of (I-27b) as a clear colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.59 (1H), 6.90 (1H), 4.17 (2H), 2.11 (1H), 1.23 (6H).

Intermediate:1-(2-methyl-2-(triethylsilyloxy)propyl)-3-nitro-1H-pyrazole (I-27c)

Intermediate (I-27b) (948 mg, 5.12 mmol) was dissolved in anhydrousN,N-dimethyl formamide (25 mL) and cooled to 0° C. in an ice bath. Tothis was added chlorotriethylsilane (0.945 mL, 5.63 mmol) and imidazole(871 mg, 12.8 mmol). The mixture was stirred at 0° C. and then slowlyallowed to warm to room temperature and stirred for two days. Thereaction was diluted with ethyl acetate (75 mL) and washed with brine(50 mL). The aqueous layer was extracted with ethyl acetate (2×75 mL)and the combined organic layers were dried over Na₂SO₄, filtered,evaporated, then purified by silica gel flash chromatography (5-25%ethyl acetate/heptanes over 40 minutes) to afford 1.133 g of (I-27c) asa clear colorless oil; m/z 300.0 (M+H)⁺.

Intermediate: 1-(2-methyl-2-(triethylsilyloxy)propyl)-1H-pyrazol-3-amine(I-27d)

In a Parr shaker bottle was placed 10% palladium on activated carbon(145 mg) and ethanol (10 mL) followed by a solution of intermediate(I-27c) (1.125 g, 0.65 mmol) in ethanol (40 mL). The bottle was thenplaced on the Parr shaker at 40 psi of hydrogen pressure for 1 h. Thereaction was then filtered through a pad of celite and washed withethanol. Concentration in vacuo afforded 981 mg (96.9%) of (I-27d) as aclear pale green oil; m/z 270.0 (M+H)⁺.

Intermediate: benzyl 6-aminonicotinate (I-28a)

To a stirred suspension of 6-aminonicotinic acid (100 g, 0.72 mol;Aldrich Chemical Company, Inc., Milwaukee, Wis.) inN,N-dimethylformamide (700 mL) with brisk mechanical stirring was addedpotassium carbonate (150 g, 1.08 mol) and the reaction was stirred for10 min before the portionwise addition of benzyl bromide (95 mL, 0.80mol). The reaction was stirred at room temperature overnight, then thesolids were filtered off and washed thoroughly with ethyl acetate, andthe solvent was removed under vacuum. The filter cake was dissolved inwater and extracted with ethyl acetate. The residue after evaporation ofN,N-dimethylformamide was combined with the ethyl acetate extracts(total volume 2 L of ethyl acetate) and the combined organic extractswashed with brine (5×500 mL), dried (MgSO₄) and the solvent removedunder reduced pressure. The crude product was refluxed with 1:1 diethylether:hexane for 30 min then the solids filtered off (warm), washed withdiethyl ether:hexane (1:1), and dried. This solid was precipitated fromhot toluene (hot filtration required to remove dibenzylated material)and dried to afford (I-28a) (107.2 g, 65%) as an off-white solid; ¹H NMR(DMSO-d₆): δ 8.50 (1H), 7.82 (1H), 7.34-7.29 (5H), 6.84 (2H), 6.43 (1H),5.23 (2H); m/z 229.4 (M+H)⁺.

Intermediate: tert-butyl 5-bromopyridin-2-ylcarbamate (I-29a)

To a solution of 2-amino-5-bromopyridine (8.65 g, 50 mmol) in THF (100mL) was added lithium hexamethyldisilazide (105 mL, 105 mmol) undernitrogen at 0° C. After the addition, the mixture was stirred for 30mins at 0° C. At this point, (BOC)₂O (12 g, 55 mmol) was added to thereaction mixture and the mixture was stirred for another 30 mins at 0°C. TLC (petroleum ether/ethyl acetate=5:1) indicated the reaction wascomplete. The reaction mixture was washed with 1 N HCl (20 mL), and theresidue was extracted with ethyl acetate (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and evaporated invacuo. The residue was purified by chromatography on silica to afford(I-29a) (8 g, 58.6%) as a white solid.

Intermediate: butyl phosphenite (I-29b)

A mixture of anilinium hypophosphite (20 g, 0.131 mol; Aldrich ChemicalCompany, Inc., Milwaukee, Wis.) and tetrabutyl orthosilicate (28.23 g,0.088 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in THF (400mL) was refluxed for 12 hours under nitrogen. The resulting mixture wascooled to give afford (I-29b) as a solution, which was used in the nextstep directly without further purification.

Intermediate: butyl methylphosphinate (I-29c)

To a solution of crude intermediate (I-29b) (400 mL THF solution, 0.131mol) was added methyl iodide (12.44 g, 0.087 mol) and n-butyl lithium(42 mL, 0.105 mol) dropwise at −78° C. under nitrogen. After theaddition, the reaction mixture was gradually warmed to room temperature.The resulting mixture was stirred at room temperature for 12 hours. TLC(petroleum ether/ethyl acetate=1:1) indicated the reaction was complete.The mixture was washed with aq. sodium bicarbonate (50 mL) and theresidue was extracted with ethyl acetate (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and evaporated invacuo. The residue was purified by chromatography on silica to afford(I-29c) (4.3 g, 24%) as an oil; ¹H NMR (400 MHz, CDCl₃): δ 7.82 (0.5H),6.48 (0.5H), 3.88-4.09 (2H), 1.59-1.66 (2H), 1.45-1.53 (3H), 1.32-1.44(2H), 0.84-0.90 (3H).

Intermediate: tert-butyl5-(ethoxy(methyl)phosphoryl)pyridin-2-ylcarbamate (I-29d)

A mixture of intermediate (I-29c) (2.7 g, 19.8 mmol), intermediate(I-29a) (5.4 g, 19.8 mmol), triethylamine (3.0 g, 29.7 mmol), Pd(OAc)₂(0.533 g, 2.38 mmol), and triphenylphosphine (1.56 g, 5.94 mmol) inethanol (100 mL) was refluxed for 18 hours under nitrogen. TLC(dichloromethane/methanol=10:1) indicated the reaction was complete. Thereaction mixture was concentrated in vacuo, and the residue was washedwith water and extracted with ethyl acetate (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, and evaporatedin vacuo. The residue was purified by chromatography on silica to afford(I-29d) (1.8 g, 30.4%) as an oil.

Intermediate: ethyl 6-aminopyridin-3-yl(methyl)phosphinate (I-29e)

A mixture of intermediate (I-29d) (1.8 g, 0.006 mol) and trifluoroaceticacid (20 mL) in dichloromethane (30 mL) was stirred at room temperaturefor 12 hours. TLC (dichloromethane/methanol=10:1) indicated the reactionwas complete. The reaction mixture was washed with saturated aq. sodiumbicarbonate (100 mL) and the mixture was extracted with dichloromethane(20 mL×3). The combined organic phases were concentrated to afford(I-29e) (1.1 g, 91.7%) as a light yellow solid; ¹H NMR (400 MHz, CDCl₃):δ 8.26-8.27 (1H), 7.73-7.79 (1H), 6.57-6.60 (1H), 5.88 (2H), 3.96-4.06(1H), 3.77-3.85 (1H), 1.56-1.60 (3H), 1.18-1.25 (3H).

Intermediate: ethyl6-((S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl(methyl)phosphinate(I-29f)

To a solution of intermediate (I-8c) (0.6 g, 2.06 mmol) indichloromethane (20 mL) was added intermediate (I-29f) (0.41 g, 2.06mmol) and triethylamine (0.89 mL, 6.18 mmol) at room temperature, andthe mixture was stirred for 12 hours at room temperature under nitrogen.TLC (dichloromethane/methanol=10:1) indicated the reaction was complete.The reaction mixture was concentrated in vacuo, the residue was purifiedby chromatography on silica to afford (I-29f) (250 mg, 26.6%) as an oil;¹H NMR (400 MHz, CDCl₃): δ 9.98 (1H), 8.61 (1H), 8.22 (1H), 8.00 (1H),7.71 (1H), 7.51 (1H), 5.05 (1H), 4.07 (1H), 3.82 (1H), 2.14 (2H),1.39-1.78 (10H), 1.01-1.33 (5H).

Intermediate: 2,2-dimethyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (I-30a)

To a solution of salicylamide (20.0 g, 0.146 mol; Aldrich ChemicalCompany, Inc., Milwaukee, Wis.) in 2,2-dimethoxypropane (300 mL) wasadded pyridinium p-toluenesulfonate (11.0 g, 0.044 mol) and then heatedto reflux for 2 h. TLC (dichloromethane: methanol=20:1) indicated thereaction was complete. The solvent was removed and then the residue wastaken up in ethyl acetate (150 mL). The solution was washed twice withsodium bicarbonate and once with brine. The organic layer was dried andconcentrated under reduced pressure to afford (I-30a) (26.0 g, yield:93.4%) as a yellow solid, which was used to next step without anypurification.

Intermediate: 4-chloro-2,2-dimethyl-2H-benzo[e][1,3]oxazine (I-30b)

To a solution of intermediate (I-30a) (42.0 g, 0.237 mol) in POCl₃ (200mL) was added PCl₅ (71.95 g, 0.356 mol) and stirred at room temperaturefor 1 h. Then the mixture was heated to reflux overnight. The solventwas removed by distillation under atmospheric pressure and the residuewas distilled under reduced pressure (85˜86° C., 2.5 mm Hg) to affordcrude (I-30b) (10.2 g, yield: 22.7%); ¹H NMR (400 MHz, CDCl₃): δ7.55-7.62 (1H), 7.37-7.42 (1H), 6.95-7.01 (1H), 6.80-6.85 (1H),1.60-1.70 (6H).

Intermediate: (1-oxy-pyridin-3-yl)-acetic acid ethyl ester (I-30c)

A solution of ethyl 3-pyridylacetate (10.0 g, 0.061 mol; AldrichChemical Company, Inc., Milwaukee, Wis.) and m-chloroperoxybenzoic acid(36.87 g, 0.182 mol) in dichloromethane (300 mL) was stirred at RTovernight. TLC (dichloromethane: methanol=15:1) indicated the reactionwas complete. The reaction mixture was quenched with Na₂SO₃, and thenthe solvent was removed under reduced pressure to give a crude product.The crude product was purified by chromatography on silica(dichloromethane: methanol=60:1→30:1→20:1) to give crude (I-30c) (15.2g, 40.5% purity by LC-MS) as a solid.

Intermediate: ethyl2-(6-(2,2-dimethyl-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)pyridin-3-yl)acetate(I-30d)

A solution of intermediate (I-30c) (10.0 g, 55.19 mmol) and intermediate(I-30b) (10.0 g, 46.36 mmol) in 1,2-dichloroethane (100 mL) was heatedto reflux for 3 days. TLC (dichloromethane: methanol=15:1) indicated thereaction was complete. The solvent was removed under reduced pressure toafford crude (I-30d) (11.0 g, yield: 69%) as an oil, which was used inthe next step without any purification.

Intermediate: 2-(6-aminopyridin-3-yl)acetic acid hydrochloride (I-30e)

A solution of intermediate (I-30d) (11.0 g, 0.0324 mol) in conc. HCl (75mL) was refluxed overnight. The solvent was removed under reducedpressure. The residue was dried by lyophilization to give crudeintermediate (I-30e) (11.0 g) as a solid, which was put into next stepwithout any purification.

Intermediate: methyl 2-(6-aminopyridin-3-yl)acetate (I-30f)

To a solution of intermediate (I-30e) (11.0 g, 72.36 mmol) in drymethanol (80 mL) was added conc. H₂SO₄ (1.6 mL) and heated to refluxovernight. LC-MS indicated the reaction was complete. The reactionmixture was basified to pH 8.0 with sat. aq. sodium bicarbonate andextracted with ethyl acetate (30 mL×3). The combined organic layer wasdried and concentrated in vacuo to give a crude product, which waspurified by prep. HPLC to afford (I-30f) (2.2 g, yield: 18%) as a whitesolid; ¹H NMR (400 MHz, CD₃OD): δ 7.78-7.82 (1H), 7.40-7.50 (1H),6.59-6.62 (1H), 3.69-3.78 (3H), 3.50-3.60 (2H); m/z 167.3 (M+H)⁺.

Intermediate: (S)-methyl2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)acetate(I-30g)

To a solution of intermediate (I-8c) (0.33 g, 1.12 mmol) indichloromethane (20 mL) was added intermediate (I-30f) (0.223 g, 0.9mmol) and triethylamine (0.48 mL, 3.36 mmol) at room temperature, andthe mixture was stirred for 12 hours at room temperature under nitrogen.TLC (petroleum ether/ethyl acetate=1:1) indicated the reaction wascomplete. The reaction mixture was concentrated in vacuo and the residuewas purified by chromatography on silica to afford (I-30h) (220 mg,46.4%) as an oil; ¹H NMR (400 MHz, CD₃OD): δ 8.29 (1H), 8.12 (1H), 8.00(1H), 7.77 (1H), 7.45 (1H), 5.21 (1H), 3.74 (5H), 2.25 (2H), 1.80 (1H),1.70 (1H), 1.68 (3H), 1.58 (2H), 1.35 (1H), 1.22 (1H).

Intermediate: 2-methyl-2-(1-oxy-pyridin-3-yl)-propionic acid ethyl ester(I-31a)

To a solution of intermediate (I-30c) (15.2 g, 0.084 mol) in THF (250mL) was added potassium t-butoxide (18.81 g, 0.168 mmol) slowly at −20°C. and stirred for 30 minutes. Methyl iodide (23.86 g, 0.168 mol) wasadded dropwise so as to maintain the internal temperature between −20°C. to −15° C. Then the mixture was stirred at 0° C. for 12 h. LC-MSindicated the reaction was complete. The reaction mixture was pouredinto ice water (150 mL) and ethyl acetate (150 mL). The organic layerwas separated and the aqueous phase was extracted with ethyl acetate(100 mL×2). The combined organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to give a crude product, which waspurified by prep. HPLC to afford (I-31a) (4.0 g, yield: 23%) as an oil;¹H NMR (400 MHz, CD₃OD): δ 8.40-8.47 (1H), 8.30-8.37 (1H), 7.70-7.80(1H), 7.52-7.61 (1H), 4.08-4.15 (2H), 1.52-1.63 (6H), 1.12-1.20 (3H).

Intermediate: ethyl2-(6-(2,2-dimethyl-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)pyridin-3-yl)-2-methylpropanoate(I-31b)

A solution of intermediate (I-31a) (4.0 g, 0.019 mol) and intermediate(I-30b) (3.135 g, 0.016 mol) in 1,2-dichloroethane (50 mL) was heated toreflux for 3 days. TLC (dichloromethane: methanol=15:1) indicated thereaction was complete. The solvent was removed under reduced pressure togive a crude product, which was purified by flash chromatography(dichloromethane: methanol=80:1→60:1→30:1→20:1) to afford impure (I-31b)(3.68 g, 48.5% purity by LC-MS) as a solid. Intermediate:2-(6-aminopyridin-3-yl)-2-methylpropanoic acid hydrochloride (I-31c)

A solution of intermediate (I-31b) (3.68 g, 0.01 mol) in conc. HCl (30mL) was refluxed overnight. The solvent was removed under reducedpressure. The residue was dried by lyophilization to afford (I-31c) (3.4g) as a solid, which was put into next step without any purification.

Intermediate: methyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate (I-31 d)

To a solution of intermediate (I-31c) (3.4 g, 0.019 mmol) in drymethanol (25 mL) was added conc. H₂SO₄ (0.5 mL) and heated to refluxovernight. LC-MS indicated the reaction was complete. The reactionmixture was basified to pH 8.0 with sat. aq. sodium bicarbonate andextracted with ethyl acetate (30 mL×3). The combined organic layer wasdried over Na₂SO₄ and concentrated in vacuo to give a crude product,which was purified by prep. HPLC to afford (I-31d) (0.5 g, yield: 14%)as a white solid; ¹H NMR (400 MHz, CD₃OD): δ 7.80-7.90 (1H), 7.46-7.51(1H), 6.53-6.60 (1H), 3.60-3.70 (3H), 1.48-1.60 (6H); m/z 195.3 (M+H)⁺.

Intermediate: (S)-methyl2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)-2-methylpropanoate(I-31e)

To a solution of intermediate (I-8c) (0.26 g, 0.88 mmol) indichloromethane (10 mL) was added intermediate (I-31d) (0.171 g, 0.88mmol) and triethylamine (0.38 mL, 2.64 mmol) at room temperature, andthe mixture was stirred for 12 hours at room temperature under nitrogen.TLC (petroleum ether/ethyl acetate=1:1) indicated the reaction wascomplete. The reaction mixture was concentrated in vacuo, the residuewas purified by chromatography on silica to afford (I-31 e) (240 mg,60.2%) as a light yellow solid; ¹H NMR (400 MHz, CD₃OD): δ 8.37 (1H),8.12 (1H), 8.05 (1H), 7.88 (1H), 7.84 (1H), 5.18 (1H), 3.72 (3H), 2.22(2H), 1.85 (1H), 1.80 (1H), 1.72 (3H), 1.67 (6H), 1.61 (2H), 1.38 (1H),1.28 (1H).

Intermediate:(S)-3-cyclopentyl-N-(5-nitropyridin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide(I-32a)

To a solution of intermediate (I-8c) (2.13 g, 7.2 mmol) indichloromethane (40 mL) was added 2-amino-5-nitropyridine (1.0 g, 7.2mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) and triethylamine(3.12 mL, 21.6 mmol) at room temperature, and the mixture was stirredfor 12 hours at room temperature under nitrogen. TLC (petroleumether/ethyl acetate=1:1) indicated the reaction was complete. Thereaction mixture was concentrated in vacuo, the residue was purified bychromatography on silica to afford (I-32a) (1.1 g, 38.7%) as a lightyellow solid.

Intermediate:(S)—N-(5-aminopyridin-2-yl)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide(I-32b)

To a solution of intermediate (I-32a) (0.62 mg, 1.56 mmol) inN,N-dimethylformamide (20 mL) was added zinc (1.02 g, 15.6 mmol) and asolution of FeCl₃ (2.53 mg, 15.6 mmol) in water (20 mL) at roomtemperature. The mixture was heated at 100° C. for 3 hours undernitrogen. TLC (petroleum ether/ethyl acetate=1:1) indicated the reactionwas complete. The reaction mixture was filtered, and the filtrate wasconcentrated in vacuo. The residue was washed with water (20 mL) and themixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and evaporated invacuo to afford crude (I-32b) (0.58 g, 101.2%) as a light yellow solid,which was used in the next step directly.

Intermediate: (S)-ethyl2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-ylamino)-2-oxoacetate(I-32c)

To a solution of intermediate (I-32b) (crude 0.35 g, 0.95 mmol) indichloromethane (20 mL) was added ethyl chlorooxoacetate (130 mg, 0.95mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) and triethylamine(0.41 mL, 2.85 mmol) at room temperature, and the mixture was stirredfor 12 hours at room temperature under nitrogen. TLC (petroleumether/ethyl acetate=1:1) indicated the reaction was complete. Thereaction mixture was concentrated in vacuo, the residue was purified bychromatography on silica to afford impure (I-32c) (130 mg, 29.2%) as anoil; ¹H NMR (400 MHz, CDCl₃): δ 8.83 (1H), 8.52 (1H), 8.20 (2H), 8.02(1H), 7.63 (1H), 7.45 (1H), 4.69 (1H), 4.40 (2H), 2.15 (2H), 1.40-1.65(7H), 1.35 (3H), 1.14 (2H).

Intermediate:(S)-1-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-ylamino)-2-methyl-1-oxopropan-2-ylacetate (I-33a)

To a solution of intermediate (I-32b) (crude 1.0 g, 2.72 mmol) indichloromethane (20 mL) was added 1-chlorocarbonyl-1-methylethyl acetate(448 mg, 2.72 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) andtriethylamine (1.17 mL, 8.16 mmol) at room temperature, and the mixturewas stirred for 12 hours at room temperature under nitrogen. TLC(petroleum ether/ethyl acetate=1:1) indicated the reaction was complete.The reaction mixture was concentrated in vacuo and the residue waspurified by chromatography on silica to afford (I-33a) (350 mg, 26.1%)as an oil; ¹H NMR (400 MHz, CD₃OD): δ 8.51 (1H), 8.09 (1H), 7.95 (2H),7.86 (1H), 5.13 (1H), 2.20 (2H), 2.10 (3H), 1.82 (1H), 1.75 (1H),1.52-1.74 (11H), 1.37 (1H), 1.18 (1H).

Intermediate:(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)propanoic acid(I-34a)

To a solution of intermediate (I-7a2) (0.63 g, 2.0 mmol) in THF (6.3 mL)and water (6.3 mL) was added lithium hydroxide monohydrate (0.252 g,6.01 mmol) portionwise at room temperature. After the addition, themixture was stirred for 2 hours at room temperature. TLC (petroleumether/ethyl acetate=1:1) indicated the reaction was complete. Thereaction mixture was acidified with 0.5 N aq. HCl and the mixture wasextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and evaporated in vacuo to affordcrude (I-34a) (0.55 g, 91.7%) as an oil, which was used in the next stepdirectly.

Intermediate:(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)propanoylchloride (I-34b)

To a solution of intermediate (I-34a) (0.35 g, 1.17 mmol) indichloromethane (10 mL) was added oxalyl chloride (0.443 g, 3.49 mmol)and N,N-dimethylformamide (1 drop) at room temperature. The mixture wasstirred for 2 hours at room temperature. TLC (petroleum ether/ethylacetate=1:1) indicated the reaction was complete. The reaction mixturewas concentrated in vacuo. The residue was chased with dichloromethanetwo times and concentrated in vacuo to afford crude (I-34b) (0.35 g,94.33%) as an oil, which was used in the next step directly.

Intermediate: (S)-benzyl6-(3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinate(I-34c1)

To a solution of intermediate (I-34b) (0.35 g, 1.09 mmol) indichloromethane (10 mL) was added intermediate (I-28a) (0.25 g, 1.09mmol) and triethylamine (0.47 mL, 3.29 mmol) at room temperature, andthe mixture was stirred for 12 hours at room temperature under nitrogen.TLC (petroleum ether/ethyl acetate=1:1) indicated the reaction was notcomplete. The reaction mixture was concentrated in vacuo, diluted with0.5 N aq. HCl (10 mL), and extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andevaporated in vacuo. The residue was purified by chromatography onsilica to afford (I-34c1) (100 mg, 17.82%) as an oil.

Intermediates (S)-benzyl6-(3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinate(I-34c2) and (S)-benzyl6-(2-(4-(cyclobutylsulfonyl)-1H-imidazol-1-yl)-3-cyclopentylpropanamido)nicotinate(I-34c3) were prepared in an analogous manner to that described for thesynthesis of Intermediate I-34c1, above, using appropriate startingmaterials (e.g., I-7a1 or I-34e, respectively).

Intermediate: cyclobutanethiol (I-34d)

To a solution of magnesium (0.87 g, 36.2 mmol) in THF (20 mL) was addedcyclobutyl bromide (5.0 g, 37 mmol; Aldrich Chemical Company, Inc.,Milwaukee, Wis.) dropwise at 50° C. After the addition, the mixture wasrefluxed for 2 hours, at which point the magnesium appeared completelyconsumed. The mixture was cooled to 0° C., sulfur (0.95 g, 29.6 mmol)was added portionwise to the mixture, and the resulting mixture wasstirred at 50° C. for 2 hours. The mixture was cooled to 0° C. andlithium aluminum hydride (0.76 g, 19.95 mmol) was added portionwise tothe mixture. The resulting mixture was refluxed for 30 mins. The mixturewas quenched with aq. ammonium chloride (20 mL), 1 N HCl (20 mL) wasadded, and extracted with diethyl ether (20 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and filtered to give acrude solution of intermediate (I-34d) in THF and diethyl ether, whichwas used in the next step directly.

Intermediate: 1,2-dicyclobutyldisulfane (I-34e)

To a crude solution of intermediate (I-34d) in THF and diethyl ether wasadded a solution of sodium (0.562 g, 0.024 mol) in ethanol dropwise,followed by iodine (I₂, 5.6 g, 0.022 mol). After the addition, themixture was stirred for 1 hour at room temperature. TLC (petroleumether/ethyl acetate=5:1) indicated the reaction was complete. Themixture was quenched with aq. NaHSO₃ (50 mL) and extracted with diethylether (20 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and evaporated in vacuo. The residue was purified bychromatography on silica to afford (I-34e) (2.1 g, 32.6%) as an oil; ¹HNMR (400 MHz, CDCl₃): δ 3.48 (2H), 2.21 (4H), 2.08 (4H), 1.85 (4H).

Intermediate: N,N-dimethyl-1H-imidazole-4-sulfonamide (I-35a)

To a solution of 1H-imidazole-4-sulfonyl chloride (0.5 g, 3.0 mmol;Matrix Scientific, Columbia, S.C.) in dichloromethane (10 mL) was addeddimethylamine hydrochloride (0.245 g, 3.0 mmol) and triethylamine (1.3mL, 9.0 mmol) at room temperature. The mixture was stirred for 16 hoursat room temperature. TLC (petroleum ether/ethyl acetate=0:1) indicatedthe reaction was complete. The reaction mixture was washed with aq.ammonium chloride (30 mL) and extracted with dichloromethane:methanol=4:1 (3×50 mL). The combined organic phases were concentratedand precipitated from methanol to afford (I-35a) (0.36 g, 68.2%) as awhite solid; ¹H NMR (400 MHz, CD₃OD): δ 7.74 (1H), 7.61 (1H), 2.68 (6H).

Intermediate:(S)-3-cyclopentyl-2-(4-dimethylsulfamoyl-imidazol-1-yl)-propionic acidmethyl ester (I-35b)

To a solution of intermediate (I-35a) (0.36 g, 2.045 mmol) in THF (10mL) was added lithium hexamethyldisilazide (1.84 mL, 1.84 mmol) dropwiseat room temperature. After the addition, the mixture was stirred for 1hour at room temperature and intermediate (I-1c) (0.622 g, 2.045 mmol)was added. The resulting mixture was stirred at room temperature for 12hours. TLC (petroleum ether/ethyl acetate=1:1) indicated the reactionwas complete. The mixture was quenched with aq. ammonium chloride (30mL) and the residue was extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andevaporated in vacuo. The residue was purified by chromatography onsilica to afford (I-35b) (580 mg, 86.4%) as an oil; ¹H NMR (400 MHz,CD₃OD): δ 87.96 (1H), 7.90 (1H), 5.17 (1H), 3.78 (3H), 2.76 (6H), 2.20(2H), 1.72 (1H), 1.68 (3H), 1.55 (3H), 1.23 (1H), 1.10 (1H).

Intermediate:(S)-3-cyclopentyl-2-(4-dimethylsulfamoyl-imidazol-1-yl)-propionic acid(I-35c)

To a solution of intermediate (I-35b) (0.35 g, 1.06 mmol) in THF (3.5mL) and water (3.5 mL) was added lithium hydroxide monohydrate (133 mg,3.18 mmol) portionwise at room temperature. After the addition, themixture was stirred for 2 hours at room temperature. TLC (petroleumether/ethyl acetate=1:1) indicated the reaction was complete. Thereaction mixture was acidified with 0.5 N aq. HCl and the mixture wasextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and evaporated in vacuo to affordcrude (I-35c) (0.32 g, 95.5%) as a light yellow solid.

Intermediate:(S)-3-cyclopentyl-2-(4-dimethylsulfamoyl-imidazol-1-yl)-propionylchloride (I-35d)

To a solution of intermediate (I-35c) (0.33 g, 1.04 mmol) indichloromethane (10 mL) was added oxalyl chloride (0.397 g, 3.13 mmol)and N,N-dimethylformamide (1 drop) at room temperature. The mixture wasstirred for 2 hours at room temperature. TLC (petroleum ether/ethylacetate=1:1) indicated the reaction was complete. The reaction mixturewas concentrated in vacuo, the residue was chased with dichloromethanetwo times, and concentrated in vacuo to afford crude (I-35d) (0.35 g,100%) as an oil, which was used in the next step directly.

Intermediate:6-[(S)-3-cyclopentyl-2-(4-dimethylsulfamoyl-imidazol-1-yl)-propionylamino]-nicotinicacid benzyl ester (I-35e)

To a solution of intermediate (I-35d) (0.35 g, 1.09 mmol) indichloromethane (15 mL) was added intermediate (I-28a) (0.24 g, 1.04mmol) and pyridine (0.25 mL, 3.13 mmol) at room temperature, and themixture was stirred for 12 hours at room temperature under nitrogen. TLC(petroleum ether/ethyl acetate=1:1) indicated the reaction was notcomplete. The reaction mixture was concentrated in vacuo, 0.5 N aq. HCl(10 mL) was added, and extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andevaporated in vacuo. The residue was purified by chromatography onsilica to afford (I-35e) (80 mg, 14.6%) as an oil.

Intermediate: methyl 2-(4-(trifluoromethyl)-1H-imidazol-1-yl)acetate(I-36a)

To a solution of 4-(trifluoromethyl)-1H-imidazole (10.0 g, 73.5 mmol) inTHF (75 mL) at 0° C. was added sodium hydride (60% in mineral oil, 3.25g, 80.8 mmol) under nitrogen. The mixture was stirred at 0° C. for 30min. Methyl bromoacetate (1.67 mL, 17.6 mmol) was added and the reactionwas stirred for 3 h at room temperature. LC-MS showed the reaction wascomplete. The solvent was removed under reduced pressure. The crudematerial was redissolved in diethyl ether and washed with sat. aq.ammonium chloride and 1N HCl aqueous solution. The combined aqueouslayer was reextracted with ethyl acetate three times. The combinedorganic layer was dried over MgSO₄, filtered, and evaporated to amixture of solid and oil. The crude was filtered to remove most of theoil, and the solid was washed with heptane. This yellow solid wastriturated in a minimum amount of diethyl ether to wash off the yellowimpurities. The material was filtered and the solid was retrituratedwith diethyl ether again. The filtrate was concentrated and the previoustrituration steps were repeated. This afforded (I-36a) as a white solid(9.33 g, 61%); ¹H NMR (400 MHz, CDCl₃): δ 7.53 (1H), 7.30 (1H), 4.73(2H), 3.81 (3H); m/z 209.0 (M+H)⁺.

Intermediate: methyl3-(1-methyl-1H-imidazol-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)acrylate(I-36b)

To a 0.2 M solution of intermediate (I-36a) in THF was added 1.1 eq1-methyl-1H-imidazole-4-carbaldehyde (Ryan Scientific, Inc., Mt.Pleasant, S.C.), and this solution was then cooled to 0° C. To thissolution was added 0.5 equivalents of potassium t-butoxide as a 1 Msolution in THF, and the reaction was allowed to slowly warm to RT.After 18 h the solution was acidified with 1N HCl, brine was added, andextracting three times with ethyl acetate. The resulting organic layerswere then combined, dried over sodium sulfate and concentrated to affordcrude (I-36b). This material was taken forward crude.

Intermediate: methyl3-(1-methyl-1H-imidazol-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate(I-36c1)

Crude intermediate (I-36b) was dissolved in THF. To this solution wasthen added 30 equivalents of water, 10 equivalents of ammonium formate,and finally 0.1 equivalent of palladium on carbon (10%). This mixturewas then heated to reflux. After 60 min the reaction was worked-up byfiltering through a syringe filter, washing with ethanol, drying overmagnesium sulfate, and concentrating down to afford crude (I-36c1) whichwas used in the next step without purification.

Intermediates methyl3-(4-ethylthiazol-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate,(I-36c2), and methyl3-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate(I-36c3) were prepared in an analogous manner to that described for thesynthesis of Intermediate (I-36c1) from 4-ethylthiazole-2-carbaldehyde(Aces Pharma, Inc., Branford, Conn.) and1-methyl-1H-pyrazole-3-carbaldehyde (Ryan Scientific, Inc., Mt.Pleasant, S.C.), respectively.

EXAMPLES

The compounds provided below may be prepared using procedures asdescribed herein using appropriate starting materials which arecommercially available, prepared using preparations well-known to theskilled artisan, or prepared in a manner analogous to routes describedherein.

Examples I-24 of general Formula (1A-1) are provided below.

Example 1(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

To a stirred solution of 2-amino-5-picoline (57 mg, 0.531 mmol) inanhydrous toluene was added AlMe₃ (2.0 M in toluene, 0.284 mL, 0.567mmol). The mixture was stirred at room temperature for 35 minutes, andthen a solution of Intermediate (I-4a1) (83 mg, 0.25 mmol) indichloroethane (2 mL) was added. The reaction mixture was heated at 80°C. for 48 hours and then cooled to room temperature and saturatedaqueous potassium sodium tartrate tetrahydrate was added. The mixturewas extracted with CH₂Cl₂. The combined extracts were dried over MgSO₄and eluted with flash column chromatography (SiO₂, 0-100% ethylacetate/heptane) to afford the title compound. ¹H NMR (400 MHz, d₆-DMSO)δ 10.94 (1H), 8.52 (1H), 8.15 (1H), 7.85-7.89 (2H), 7.57-7.60 (1H),5.33-5.37 (1H), 3.23-3.28 (1H), 2.22-2.29 (4H), 2.01-2.08 (1H),1.43-1.65 (5H), 1.32-1.43 (2H), 1.20-1.29 (1H), 1.13-1.16 (6H),1.02-1.10 (1H); m/z 405.0 (M+H)⁺, 403.1 (M−H)⁻.

Example 2(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(pyrazin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 2 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 2-aminopyrazine. ¹H NMR (400 MHz, CDCl₃) δ9.48 (1H), 9.37 (1H), 8.38 (1H), 8.27 (1H), 8.09 (1H), 7.98 (1H), 5.03(1H), 4.11 (1H), 3.14 (1H), 2.20-2.39 (2H), 2.04 (2H), 1.45-1.69 (4H),1.33 (6H), 1.25 (2H); m/z 392.2 (M+H)⁺.

Example 3(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 3 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 2-amino-5-trifluoromethylpyridine. ¹H NMR(400 MHz, CDCl₃) δ 9.40 (1H), 8.56 (1H), 8.30 (1H), 8.03 (2H), 7.94(1H), 4.98 (1H), 3.20 (1H), 2.32-2.42 (1H), 2.19-2.29 (1H), 1.72-1.85(1H), 1.48-1.71 (4H), 1.30-1.38 (6H), 1.17-1.30 (2H), 1.04-1.16 (2H);m/z 459.1 (M+H)⁺.

Example 4(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(pyrimidin-4-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 4 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 4-aminopyrimidine. ¹H NMR (400 MHz, CDCl₃) δ9.39 (1H), 8.88 (1H), 8.65 (1H), 8.10 (1H), 8.01 (1H), 7.98 (1H), 4.95(1H), 3.20 (1H), 2.37 (1H), 2.20 (1H), 1.76 (1H), 1.58-170 (6H), 1.36(6H), 1.18 (1H), 1.02 (1H); m/z 392.1 (M+H)⁺.

Example 5(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(pyrimidin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 5 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 2-aminopyrimidine. ¹H NMR (400 MHz, CDCl₃) δ9.91 (1H), 8.67 (1H), 8.66 (1H), 8.18 (1H), 7.86 (1H), 7.08 (1H), 3.20(1H), 2.22 (2H), 1.81 (1H), 1.58-166 (6H), 1.30-132 (6H), 1.23 (2H),1.02 (1H); m/z 392.2 (M+H)⁺.

Example 6(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methylpyrazin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 6 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 2-amino-5-methylpyridine. ¹H NMR (400 MHz,CDCl₃) δ 9.30 (1H), 9.20 (1H), 8.09 (1H), 8.06 (1H), 7.94 (1H), 5.02(1H), 3.14-3.19 (1H), 2.49 (3H), 2.21-2.35 (2H), 1.76 (1H), 1.44-1.60(6H), 1.29-131 (6H), 1.16-1.20 (1H), 1.08-1.14 (1H); m/z 406.2 (M+H)⁺.

Example 7(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 7 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 3-amino-1-methylpyrazole. ¹H NMR (400 MHz,d₆-DMSO) δ 10.96 (1H), 8.48 (1H), 7.83 (1H), 7.53 (1H), 6.37 (1H),5.20-5.23 (1H), 3.71 (3H), 3.22-3.28 (1H), 2.16-2.23 (1H), 1.99-2.06(1H), 1.44-1.64 (5H), 1.36-1.44 (2H), 1.20-1.26 (1H), 1.13-1.16 (6H),0.99-1.10 (1H); m/z 394.0 (M+H)⁺, 392.1 (M−H)⁻.

Example 8(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanamide

Formula (1A-1) wherein R^(1a) is methyl and R⁴ is

Example 8 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a2 and 2-amino-5-methylpyridine. ¹H NMR (400 MHz,d₆-DMSO) δ 10.97 (1H), 8.55 (1H), 8.16 (1H), 7.88-7.91 (2H), 7.57-7.60(1H), 5.34-5.36 (1H), 3.20 (3H), 2.11-2.24 (4H), 2.01-2.08 (1H),1.58-1.64 (2H), 1.44-1.58 (3H), 1.36-1.44 (2H), 1.20-1.30 (1H),1.04-1.11 (1H); m/z 376.9 (M+H)⁺, 375.1 (M−H)⁻.

Example 9(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanamide

Formula (1A-1) wherein R^(1a) is methyl and R⁴ is

Example 9 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a2 and 3-amino-1-methylpyrazole. ¹H NMR (400 MHz,d₆-DMSO) δ 10.98 (1H), 8.51 (1H), 7.90 (1H), 7.53 (1H), 6.38 (1H),5.18-5.22 (1H), 3.71 (3H), 3.19 (3H), 2.11-2.19 (1H), 1.99-2.06 (1H),1.60-1.68 (2H), 1.45-1.60 (3H), 1.17-1.45 (2H), 1.17-1.26 (1H),1.03-1.10 (1H); m/z 366.0 (M+H)⁺, 364.1 (M−H)⁻.

Example 10(S)-3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is methyl and R⁴ is

Example 10 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a2 and 2-amino-5-trifluoromethylpyridine. ¹H NMR(400 MHz, CDCl₃) δ 9.31 (1H), 8.55 (1H), 8.24-8.28 (1H), 8.02-8.07 (2H),7.90-7.97 (1H), 4.89-4.96 (1H), 3.17 (3H), 2.30-2.40 (1H), 2.18-2.28(1H), 1.44-1.85 (7H), 1.15-1.28 (1H), 1.03-1.17 (1H); m/z 430.9 (M+H)⁺,429.0 (M−H)⁻.

Example 11(S)-3-cyclopentyl-N-(1-ethyl-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanamide

Formula (1A-1) wherein R^(1a) is methyl and R⁴ is

Example 11 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a2 and 3-amino-1-ethylpyrazole. ¹H NMR (400 MHz,CDCl₃) δ 8.81 (1H), 8.06 (1H), 7.98 (1H), 7.29 (1H), 6.60 (1H),5.84-4.88 (1H), 4.00-4.08 (2H), 3.13 (3H), 2.18-2.35 (2H), 1.39-1.82(10H), 1.01-1.24 (2H); m/z 380.0 (M+H)⁺, 378.1 (M−H)⁻.

Example 12(S)—N-(1-benzyl-1H-pyrazol-3-yl)-3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanamide

Formula (1A-1) wherein R^(1a) is methyl and R⁴ is

Example 12 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a2 and 3-amino-1-benzylpyrazole. ¹H NMR (400 MHz,CDCl₃) δ 8.81 (1H), 8.03 (1H), 7.98 (1H), 7.28-7.36 (4H), 7.13-7.18(1H), 6.64 (1H), 5.17 (2H), 4.83-4.88 (1H), 3.11 (3H), 2.18-2.31 (2H),1.72-1.81 (1H), 1.42-1.71 (6H), 1.01-1.22 (2H); LCMS for C₂₂H₂₇N₅O₃S₁m/z 442.0 (M+H)⁺, 440.0 (M−H)⁻.

Example 13(S)-3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)-N-(pyrimidin-4-yl)propanamide

Formula (1A-1) wherein R^(1a) is methyl and R⁴ is

Example 13 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a2 and 4-aminopyrimidine. ¹H NMR (400 MHz, CDCl₃) δ9.25 (1H), 8.88 (1H), 8.62-8.65 (1H), 8.09-8.11 (1H), 8.03 (2H),4.86-4.91 (1H), 3.15 (3H), 2.30-2.39 (1H), 2.17-2.24 (1H), 1.75-1.83(1H), 1.44-1.74 (6H), 1.02-1.23 (2H); m/z 364.0 (M+H)⁺, 362.0 (M−H)⁻.

Example 14(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanamide

Formula (1A-1) wherein R^(1a) is methyl and R⁴ is

Example 14 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a2 and 2-amino-5-methylpyrazine. ¹H NMR (400 MHz,CDCl₃) δ 9.35 (1H), 9.01 (1H), 8.12 (1H), 8.07 (1H), 8.02 (1H),4.89-4.97 (1H), 3.12 (3H), 2.51 (3H), 2.28-2.40 (1H), 2.19-2.25 (1H),1.75-1.82 (1H), 1.42-1.75 (6H), 1.16-1.24 (1H), 1.02-1.16 (1H); m/z378.0 (M+H)⁺, 376.0 (M−H)⁻.

Example 15(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(isoxazol-3-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 15 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 3-aminoisoxazole. m/z 381 (M+H)⁺.

Example 16(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(pyridin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 16 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 2-aminopyridine. m/z 391 (M+H)⁺.

Example 17(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)-N-(quinolin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 17 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 2-aminoquinoline. m/z 441 (M+H)⁺.

Example 18(S)-3-cyclopentyl-N-(1-ethyl-1H-pyrazol-3-yl)-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)propanamide

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 18 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 3-amino-1-ethylpyrazole. ¹H NMR (400 MHz,CDCl₃) δ 9.16 (1H), 9.12 (1H), 8.05 (1H), 7.90 (1H), 7.26 (1H), 6.59(1H), 5.27 (1H), 4.93-4.97 (1H), 4.00-4.05 (2H), 3.10-3.18 (1H),2.14-2.28 (2H), 1.61-1.74 (1H), 1.38-1.55 (7H), 1.29-131 (6H), 1.12-1.17(1H), 1.01-1.10 (1H); m/z 408.2 (M+H)⁺.

Example 19(S)—N-(1-benzyl-1H-pyrazol-3-yl)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-pyrazol-1-yl)propanamide,

Formula (1A-1) wherein R^(1a) is isopropyl and R⁴ is

Example 19 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a1 and 3-amino-1-benzylpyrazole. ¹H NMR (400 MHz,CDCl₃) δ 9.00 (1H), 8.00 (1H), 7.90 (1H), 7.28-7.79 (4H), 7.14-7.16(2H), 6.67 (1H), 5.28 (2H), 4.88-4.92 (1H), 3.11-3.18 (1H), 2.02-2.30(2H), 1.67-1.76 (1H), 1.45-1.60 (6H), 1.30-132 (6H), 1.92 (1H),1.06-1.18 (1H); m/z 470.3 (M+H)⁺.

Example 20(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-pyrazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)propanamide

Formula (1A-1) wherein R^(1a) is ethyl and R⁴ is

Example 20 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a3 and 3-amino-1-methylpyrazole. ¹H NMR (400 MHz,CDCl₃) δ 9.37 (1H), 8.11 (1H), 7.90 (1H), 7.22 (1H), 6.59 (1H),4.95-4.99 (1H), 3.77 (3H), 3.09-3.14 (2H), 2.16-2.23 (2H), 1.40-1.75(7H), 1.20-1.31 (3H), 0.98-1.12 (2H); m/z 380.5 (M+H)⁺.

Example 21(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is ethyl and R⁴ is

Example 21 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a3 and 2-amino-5-methylpyridine. ¹H NMR (400 MHz,CDCl₃) δ 9.42 (1H), 8.13 (2H), 8.03 (1H), 7.94 (1H), 7.49 (1H),4.96-4.99 (1H), 3.10-3.16 (2H), 2.27 (3H), 2.14-2.25 (1H), 1.40-1.72(8H), 1.29-1.33 (3H), 1.00-1.16 (2H); m/z 391.5 (M+H)⁺.

Example 22(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methylpyrazin-2-yl)propanamide

Formula (1A-1) wherein R^(1a) is ethyl and R⁴ is

Example 22 was synthesized in an analogous manner to that of Example 1from Intermediate I-4a3 and 2-amino-5-methylpyrazine. ¹H NMR (400 MHz,CDCl₃) δ 9.31 (1H), 9.21 (1H), 8.08 (2H), 7.97 (1H), 4.97-5.00 (1H),3.11-3.17 (2H), 2.50 (3H), 2.24-2.32 (1H), 1.44-1.77 (8H), 1.28-1.32(3H), 1.07-1.21 (2H); m/z 390.5 (M−H)⁺.

Example 23 (S)-benzyl6-(3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanamido)nicotinate

Formula (1A-1) wherein R^(1a) is methyl and R⁴ is

Intermediate (I-23a) (165 mg, 0.576 mmol) was stirred in drydichloromethane (6 mL) at room temperature under nitrogen. One drop ofDMF was added followed by oxalyl chloride (0.10 mL, 1.15 mmol). Afterbubbling subsided, the reaction was left stirring for 90 minutes andthen evaporated. The residue was dissolved in two successive portions of1,2-dichloroethane and evaporated to remove excess oxalyl chloride, andthen dissolved in dry dichloromethane (4 mL). Intermediate (I-28a) (105mg, 0.46 mmol) and pyridine (0.10 mL, 1.24 mmol) were stirred in drydichloromethane (6 mL) and added to the acid chloride solution. Thereaction was left to stir for 18 hours, diluted with dichloromethane and10% aqueous potassium carbonate, and the organic layer was separated,washed with brine, dried over sodium sulfate, filtered, and evaporated.The residue was purified by silica gel chromatography, using a 12 gpre-packed column, eluting with 10% ethyl acetate/heptane, lineargradient to 70% ethyl acetate. The product fractions were combined,evaporated, and dried under high vacuum to afford the title compound(182.9 mg, 0.368 mmol, 80%) as a white glass. ¹H NMR (400 MHz, CDCl₃) δ9.28 (1H), 8.93 (1H), 8.30-8.33 (1H), 8.19-8.21 (1H), 8.07 (1H), 8.03(1H), 7.34-7.44 (5H), 5.36 (2H), 4.90-4.94 (1H), 3.13 (s, 3H), 2.31-2.35(1H), 2.21-2.25 (1H), 1.48-1.78 (7H), 1.07-1.24 (2H); m/z 497.2 (M+H)⁺.

Example 24(S)-6-(3-cyclopentyl-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)propanamido)nicotinicacid

Formula (1A-1) wherein R^(1a) is methyl and R⁴ is

The compound of Example 23 (182 mg, 0.367 mmol) was dissolved in ethylacetate (3 mL) and ethanol (6 mL) in a 250 mL Parr bottle. 10% Palladiumon carbon (20 mg) was added, and the mixture was shaken under 50 psihydrogen for 90 minutes. The reaction was filtered, evaporated, anddried under high vacuum to afford the title compound (134.3 mg, 0.33mmol, 90%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.44 (1H), 8.83 (1H), 8.57(1H), 8.23-8.26 (1H), 8.09-8.11 (1H), 7.93 (1H), 5.38-5.42 (1H), 3.20(3H), 2.21-2.29 (1H), 2.03-2.10 (1H), 1.38-1.88 (7H), 1.20-1.31 (1H),1.04-1.11 (1H); m/z 404.9 (M−H)⁻.

Examples 25-27 of general Formula (1A-2) are provided below.

Example 25(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(3-(methylsulfonyl)-1H-1,2,4-triazol-1-yl)propanamide

Formula (1A-2) wherein R^(1a) is methyl and R⁴ is

To a stirred solution of 2-amino-5-picoline (33 mg, 0.307 mmol) inanhydrous toluene was added AlMe₃ (2.0 M in toluene, 0.164 mL, 0.327mmol). The mixture was stirred at room temperature for 45 minutes, andthen added the solution of 44 mg (0.15 mmol) of Intermediate I-5b indichloroethane (2 mL). The reaction mixture was heated at 80° C. for 18hours and then cooled to room temperature and saturated aqueouspotassium sodium tartrate tetrahydrate was added. The mixture wasextracted with CH₂Cl₂. The combined extracts were dried over MgSO₄ andflash column chromatography (SiO₂, heptane/ethyl acetate, 25 to 80%) toafford the title compound. ¹H NMR (400 MHz, d₆-DMSO) δ 11.13 (1H), 9.08(1H), 8.18 (1H), 7.85-7.92 (1H), 7.58-7.63 (1H), 5.41-5.50 (1H), 3.28(3H), 2.20-2.31 (4H), 2.11-2.20 (1H), 1.46-1.68 (5H), 1.38-1.46 (2H),1.21-1.32 (1H), 1.02-1.19 (1H); m/z 378.1 (M+H)⁺, 376.1 (M−H)⁻.

Example 26(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)-1H-1,2,4-triazol-1-yl)propanamide

Formula (1A-2) wherein R^(1a) is methyl and R⁴ is

Example 26 was synthesized in an analogous manner to that of Example 25from Intermediate I-5b and 3-amino-1-methylpyrazole. ¹H NMR (400 MHz,CDCl₃) δ 9.18 (1H) 8.59 (1H) 7.25 (1H) 6.57 (1H) 5.24-5.28 (1H) 3.79(3H)) 3.30 (3H) 2.19-2.29 (2H) 1.42-1.76 (5H) 1.02-1.15 (2H); m/z 365.4(M−H)⁺.

Example 27(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(3-(methylsulfonyl)-1H-1,2,4-triazol-1-yl)propanamide

Formula (1A-2) wherein R^(1a) is methyl and R⁴ is

Example 27 was synthesized in an analogous manner to that of Example 25from Intermediate I-5b and 2-amino-5-methylpyrazine. ¹H NMR (400 MHz,CDCl₃) δ 9.123 (1H), 9.03 (1H), 8.57 (1H), 8.08 (1H), 5.44-5.248 (1H),3.33 (3H), 2.49 (3H), 2.27-2.32 (2H), 1.42-1.81 (7H), 1.08-1.24 (2H);m/z 377.4 (M−H)⁺.

Examples 28-42 of general Formula (1A-3) are provided below.

Example 28(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide

Formula (1A-3) wherein R^(1a) is isopropyl and R⁴ is

To a stirred solution of 2-amino-5-picoline (36 mg, 0.332 mmol) inanhydrous toluene was added AlMe₃ (2.0 M in toluene, 0.177 mL, 0.354mmol). The mixture was stirred at room temperature for 45 minutes, andthen a solution of 52 mg (0.158 mmol) of Intermediate I-7a1 indichloroethane (2 mL) was added. The reaction mixture was heated at 80°C. for 16 hours and then cooled to room temperature and saturatedaqueous potassium sodium tartrate tetrahydrate was added. The mixturewas extracted with CH₂Cl₂. The combined extracts were dried over MgSO₄and flash column chromatography (SiO₂, ethyl acetate/heptane, 50 to100%) to afford the title compound. ¹H NMR (400 MHz, d₆-DMSO) δ 10.97(1H), 9.08 (1H), 8.17 (1H), 7.97-8.02 (2H), 7.85-7.89 (1H), 7.56-7.61(1H), 5.18-5.5.23 (1H), 3.22-3.30 (1H), 2.22 (3H), 2.02-2.22 (2H),1.32-1.64 (7H), 1.24-1.32 (1H), 1.10-1.15 (6H), 0.97-1.07 (1H); m/z404.9 (M+H)⁺, 403.0 (M−H)⁻.

Example 29(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)propanamide

Formula (1A-3) wherein R^(1a) is isopropyl and R⁴ is

Example 29 was synthesized in an analogous manner to that of Example 28from Intermediate I-7a1 and 3-amino-1-methylpyrazole. ¹H NMR (400 MHz,CDCl₃) δ 8.78 (1H), 7.90 (2H), 7.26 (2H), 6.60 (1H), 6.52 (1H), 5.31(2H), 3.79 (3H), 2.15 (2H), 1.63-1.77 (2H), 1.59 (2H), 1.47 (2H),1.34-1.40 (6H), 1.04-1.20 (1H); m/z 394.2 (M+H)⁺.

Example 30(S)-3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)-N-(5-methylpyrazin-2-yl)propanamide

Formula (1A-3) wherein R^(1a) is isopropyl and R⁴ is

Example 30 was synthesized in an analogous manner to that of Example 28from Intermediate I-7a1 and 2-amino-5-methylpyrazine. ¹H NMR (400 MHz,CDCl₃) δ 9.36 (1H), 9.29 (1H), 8.10 (1H), 8.03 (2H), 5.26-5.29 (1H),3.38-3.45 (1H), 2.50 (3H), 2.08-2.19 (2H), 1.43-1.64 (5H), 1.32-1.41(8H), 1.06-1.17 (2H); m/z 406.2 (M+H)⁺.

Example 31(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)propanamide

Formula (1A-3) wherein R^(1a) is ethyl and R⁴ is

Example 31 was synthesized according to the procedure described inExample 28 from Intermediate I-7a2 and 3-amino-1-methylpyrazole. ¹H NMR(400 MHz, CDCl₃) δ 9.45 (1H) 7.92 (2H) 7.26 (1H) 6.56 (1H) 4.96-4.99(1H) 3.75 (3H) 3.24-3.29 (2H) 2.13-2.19 (1H) 1.40-1.69 (8H) 1.25-1.31(3H) 1.04-1.12 (2H); m/z 380.5 (M+H)⁺.

Example 32(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide

Formula (1A-3) wherein R^(1a) is ethyl and R⁴ is

Example 32 was synthesized according to the procedure described inExample 28 from Intermediate I-7a2 and 2-amino-5-picoline. ¹H NMR (400MHz, CDCl₃) δ 8.20 (2H), 7.86-7.94 (3H), 5.45-5.52 (1H), 3.23 (2H), 2.40(3H), 2.20-2.31 (1H), 2.07-2.17 (1H), 1.38-1.92 (7H), 1.20-1.34 (4H),1.00-1.15 (1H); m/z 391.5 (M+H)⁺.

Example 33(S)-3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)-N-(5-methylpyrazin-2-yl)propanamide

Formula (1A-3) wherein R^(1a) is ethyl and R⁴ is

Example 33 was synthesized according to the procedure described inExample 28 from Intermediate I-7a2 and 2-amino-5-methylpyrazine. ¹H NMR(400 MHz, CDCl₃) δ 9.31 (1H), 9.06 (1H), 8.11 (1H), 7.95 (1H), 7.92(1H), 5.11 (1H), 3.30 (2H), 2.52 (3H), 2.08-2.24 (2H), 1.38-1.79 (7H),1.32 (3H), 1.04-1.20 (2H); m/z 390.4 (M−H)⁻.

Example 34(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamide

Formula (1A-3) wherein R^(1a) is methyl and R⁴ is

Example 34 was synthesized according to the procedure described inExample 28 from Intermediate I-7a3 and 2-amino-5-methylpyrazine. ¹H NMR(400 MHz, DMSO-d₆) δ 9.15 (1H), 8.30-8.36 (1H), 8.02-8.07 (2H), 5.27(1H), 3.13 (3H), 2.45 (3H), 2.17-2.27 (1H), 2.05-2.16 (1H), 1.38-1.73(7H), 1.25-1.36 (1H), 1.00-1.15 (1H); m/z 376.4 (M−H)⁻.

Example 35(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamide

Formula (1A-3) wherein R^(1a) is methyl and R⁴ is

Example 35 was synthesized according to the procedure described inExample 28 from Intermediate I-7a3 and 2-amino-5-picoline. ¹H NMR (400MHz, DMSO-d₆) δ 8.17-8.19 (1H), 8.03 (1H), 8.00 (1H), 7.93 (1H),7.60-7.65 (1H), 5.23 (1H), 3.13 (3H), 2.25 (3H), 2.05-2.21 (2H),1.36-1.71 (7H), 1.24-1.35 (1H), 1.04-1.14 (1H); m/z 377.5 (M+H)⁺.

Example 36(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamide

Formula (1A-3) wherein R^(1a) is methyl and R⁴ is

Example 36 was synthesized according to the procedure described inExample 28 from Intermediate I-7a3 and 3-amino-1-methylpyrazole. ¹H NMR(400 MHz, DMSO-d₆) δ 11.02 (1H) 7.99 (1H) 7.57 (1H) 6.41 (1H) 5.09 (1H)3.74 (3H) 3.12 (3H) 2.00-2.19 (2H) 1.37 (9H); m/z 364.4 (M−H)⁻.

Example 37 (S)-benzyl6-(3-cyclopentyl-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinate

Formula (1A-3) wherein R^(1a) is methyl and R⁴ is

Intermediate (I-24a) (852 mg, 2.98 mmol) was stirred in drydichloromethane (50 mL) at room temperature under nitrogen. One drop ofDMF was added, followed by oxalyl chloride (0.65 mL, 7.5 mmol). Afterbubbling subsided, the reaction was left stirring for 90 minutes andthen evaporated. The residue was re-dissolved and re-evaporated with twosuccessive portions of 1,2-dichloroethane to remove unreacted oxalylchloride. The residue was then dissolved in dry dichloromethane (60 mL),and intermediate (I-28a) (816 mg, 3.58 mmol) and pyridine (0.65 mL, 8.0mmol) were added. The reaction was stirred at room temperature undernitrogen for 18 hours, washed twice with water and once with brine,dried over sodium sulfate, filtered, evaporated. The residue waspurified by silica gel chromatography, using a pre-packed 80 g column,and eluting with 10% ethyl acetate/heptane with a linear gradient to 70%ethyl acetate/heptane. The product fractions were combined, evaporated,and dried under high vacuum at 60° C. to afford the title compound (1.08g, 2.17 mmol, 73%) as a white glass. ¹H NMR (400 MHz, CDCl₃) δ 8.92(1H), 8.88 (1H), 8.31-8.34 (1H), 8.19-8.22 (1H), 7.89 (1H), 7.83 (1H),7.33-7.44 (5H), 5.36 (2H), 4.92-4.95 (1H), 3.21 (s, 3H), 2.15-2.19 (2H),1.45-1.76 (7H), 1.09-1.18 (2H); m/z 496.9 (M+H)⁺.

Example 38(S)-6-(3-cyclopentyl-2-(4-(methylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinicacid

Formula (1A-3) wherein R^(1a) is methyl and R⁴ is

The compound of Example 37 (1.08 g, 2.18 mmol) was dissolved in ethylacetate (10 mL) and ethanol (20 mL) in a Parr bottle. 10% Palladium oncarbon was added (200 mg), and the mixture was shaken under 30 psihydrogen for 90 minutes. The mixture was filtered, evaporated, and driedunder high vacuum to a clear glass. The glass was triturated withdiethyl ether and stirred for 1 hour. The resulting material wasfiltered, washed with ether, and dried under high vacuum at 60° C. toafford the title compound (651.1 mg, 1.60 mmol, 73%) as a white powder.¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (1H), 8.83 (1H), 8.26-8.28 (1H),8.09-8.12 (1H), 8.00-8.02 (2H), 5.24-5.28 (1H), 3.10 (3H), 2.10-2.19(2H), 1.29-1.64 (8H), 1.01-1.08 (1H); m/z 406.9 (M+H)⁺.

Example 39(S)-6-(3-cyclopentyl-2-(4-(ethylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinicacid

Formula (1A-3) wherein R^(1a) is ethyl and R⁴ is

To a solution of intermediate (I-34c1) (100 mg, 0.196 mmol) in 30 mL ofa %:1 mixture of ethanol:ethyl acetate was added Pd(OH)₂/C (50 mg) atroom temperature, and the mixture was stirred for 12 hours under 50 psiof H₂. TLC (1:1 petroleum ether/ethyl acetate) indicated the reactionwas complete. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by prep-HPLC to affordthe title compound (17.5 mg, 21.2%) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ 8.81 (1H), 8.23 (1H), 8.10 (1H), 7.95 (2H), 5.11 (1H), 3.13(2H), 2.11 (2H), 1.71 (1H), 1.58 (4H), 1.41 (2H), 1.24 (1H), 1.12 (3H),1.08 (1H); m/z 421.3 (M+H)⁺.

Example 40(S)-6-(3-cyclopentyl-2-(4-(isopropylsulfonyl)-1H-imidazol-1-yl)propanamido)nicotinicacid

Formula (1A-3) wherein R^(1a) is isopropyl and R⁴ is

To a solution of intermediate (I-34c2) (80 mg, 0.153 mmol) in 20 mL of a5:1 mixture of ethanol:ethyl acetate was added Pd(OH)₂/C (40 mg) at roomtemperature, and the mixture was stirred for 12 hours under 50 psi ofH₂. TLC (1:1 petroleum ether/ethyl acetate) indicated the reaction wascomplete. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by prep-HPLC to affordthe title compound (22.7 mg, 34.3%) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ 8.90 (1H), 8.32 (1H), 8.19 (1H), 8.03 (2H), 5.21 (1H), 3.31(1H), 2.21 (2H), 1.80 (1H), 1.65 (4H), 1.50 (2H), 1.30 (7H), 1.12 (1H);m/z 435.5 (M+H)⁺.

Example 41(S)-6-(2-(4-(cyclobutylsulfonyl)-1H-imidazol-1-yl)-3-cyclopentylpropanamido)nicotinicacid

Formula (1A-3) wherein R^(1a) is cyclobutyl and R⁴ is

To a solution of intermediate (I-34c3) (200 mg, 0.373 mmol) in 30 mL ofa 5:1 mixture of ethanol:ethyl acetate was added Pd(OH)₂/C (100 mg) atroom temperature, and the mixture was stirred for 12 hours under 50 psiof H₂. TLC (1:1 petroleum ether/ethyl acetate) indicated the reactionwas complete. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by prep-HPLC to affordthe title compound (66.5 mg, 39.9%) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ 8.89 (1H), 8.31 (1H), 8.20 (1H), 8.02 (2H), 5.21 (1H), 4.04(1H), 2.49 (2H), 2.21 (4H), 1.98 (2H), 1.80 (1H), 1.60 (6H), 1.30 (1H),1.11 (1H); m/z 447.5 (M+H)⁺.

Example 426-[(S)-3-cyclopentyl-2-(4-dimethylsulfamoyl-imidazol-1-yl)-propionylamino]-nicotinicacid

Formula (1A-3) wherein R^(1a) is dimethylamino and R⁴ is

To a solution of intermediate (I-35e) (80 mg, 0.152 mmol) in 20 mL of5:1 ethanol:ethyl acetate was added Pd(OH)₂/C (40 mg) at roomtemperature, and the mixture was stirred for 12 hours under 50 psi ofH₂. TLC (1:1 petroleum ether/ethyl acetate) indicated the reaction wascomplete. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by prep-HPLC to affordthe title compound (5.3 mg, 14.6%) as a white solid. ¹H NMR (400 MHz,CD₃OD) 58.80 (1H), 8.22 (1H), 8.08 (1H), 7.85 (2H), 5.11 (1H), 2.65(6H), 2.11 (2H), 2.21 (4H), 1.71 (1H), 1.58 (4H), 1.42 (2H), 1.21 (1H),1.08 (1H); m/z 436.4 (M+H)⁺.

Examples 43-67 of general Formula (1A-4) are provided below.

Example 43(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-4) wherein R⁴ is

To a stirred solution of 2-amino-N-methyl-pyrazole (49.1 mg, 0.506 mmol)in 3 mL anhydrous toluene was added a solution of AlMe₃ (0.270 mL, 2.00M in toluene, 0.54 mmol). After stirring for 35 minutes at roomtemperature a solution of 70 mg of Intermediate I-8a in 2 mL anhydrousdichloroethane was added. The reaction was heated to 80° C. for 18hours. The reaction mixture was cooled and stirred for several minuteswith saturated Rochelle's salt and extracted twice with ethyl acetate.The combined organics were dried over MgSO₄, filtered, and the filtratewas concentrated under reduced pressure. The residue was purified byflash chromatography on a Biotage column (SiO₂, ethyl acetate/hepatane,50 to 100%)). The purified fractions were collected, concentrated, andresidue was titurated in diethyl ether to afford the title compound. ¹HNMR (400 MHz, DMSO) 510.97 (1H), 7.91 (1H), 7.89 (1H), 7.54 (1H), 6.38(1H), 5.02-5.05 (1H), 3.71 (3H), 2.01-2.08 (2H), 1.40-1.62 (7H),1.20-1.22 (1H), 1.04-1.07 (1H); m/z 356.2 (M+H)⁺.

Example 44(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-4) wherein R⁴ is

Example 44 was synthesized in an analogous manner to that of Example 43from Intermediate I-8a and 2-amino-5-methylpyridine. ¹H NMR (400 MHz,CDCl₃) δ 9.02 (1H), 8.07 (2H), 7.69 (1H), 7.54 (2H), 4.73-4.77 (1H),2.28 (3H), 2.13-2.20 (2H), 1.45-1.67 (7H), 1.10-1.12 (2H); m/z 367.0(M+H)⁺.

Example 45(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-4) wherein R⁴ is

Example 45 was synthesized in an analogous manner to that of Example 43from Intermediate I-8a and 2-amino-5-methylpyrazine. ¹H NMR (400 MHz,CDCl₃) δ 9.34 (1H), 8.65 (1H), 8.11 (1H), 7.72 (1H), 7.53 (1H),4.83-4.86 (1H), 2.52 (3H), 2.21-2.24 (2H), 2.17 (1H), 1.27-1.50 (6H),1.08-1.14 (2H); m/z 368.0 (M+H)⁺.

Example 46 (S)-methyl6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate

Formula (1A-4) wherein R⁴ is

To a stirred solution of Intermediate (I-8b) (328.5 mg, 1.189 mmol) inanhydrous dichloromethane (12 mL) at room temperature under nitrogen wasadded oxalyl chloride followed by 1 drop of DMF. The reaction bubbledand then subsided. It was left stirring for 90 minutes and thenevaporated under reduced pressure. 1,2-dichloroethane was added andconcentrated two times. The residue was then dissolved in anhydrousdichloromethane (10 mL). Methyl 6-aminonicotinate (221 mg, 1.45 mmol;Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added, followed bypyridine (0.21 mL, 2.6 mmol). The reaction was stirred overnight at roomtemperature before diluting with ethyl acetate and water. 1M aqueouspotassium dihydrogen phosphate was added. The layers were separated, andthe organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified (Combi-flash, Redi-sep 40 g, 45% ethyl acetate/heptane) toafford the title compound as an off-white glass. ¹H NMR (400 MHz, CDCl₃)δ 8.89 (1H), 8.57 (1H), 8.31-8.33 (1H), 8.24 (1H), 7.70 (1H), 7.51 (1H),4.76-4.82 (1H), 3.92 (3H), 2.16-2.21 (2H), 1.48-1.79 (7H), 1.11-1.17(2H); m/z 411.1 (M+H)⁺.

Example 47 (S)-benzyl6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate

Formula (1A-4) wherein R⁴ is

To Intermediate (I-8b) (16.28 g, 59.8 mmol) stirring in drydichloromethane (400 mL) at room temperature under nitrogen was added 2drops of DMF. Oxalyl chloride (11 mL, 130 mmol) was added dropwise.After the bubbling subsided the reaction was left stirring for 90minutes and then concentrated under reduced pressure. Two successiveportions of 1,2-dichloroethane were added and evaporated to remove allexcess oxalyl chloride. The crude acid chloride was taken up indichloromethane (150 mL) and stirred at room temperature. Intermediate(I-28a) (14.3 g, 62.5 mmol) and pyridine (10 mL, 130 mmol) were stirredin 400 mL dry dichloromethane. This was added to the acid chloridesolution, using another 50 mL dry dichloromethane to complete thetransfer. The mixture was left stirring at room temperature undernitrogen for 18 hours. The reaction was diluted with dichloromethane andwater, and 1M aqueous phosphoric acid was added. The organic layer wasseparated and washed sequentially with dilute aqueous potassiumcarbonate, and brine. This was then dried over sodium sulfate, filtered,and concentrated under reduced pressure to a glass, which was taken upin hot ethyl acetate and stirred at room temperature. A precipitateappeared at about 30 minutes. The mixture was stirred for 16 hours andthen filtered. The precipitate was washed with ethyl acetate and thendiethyl ether and dried under high vacuum at 60° C. to afford the titlecompound as a white solid (17.8 g, 36.6 mmol, 61%). The mother liquorwas evaporated and purified by silica gel chromatography on a 120 gpre-packed column, eluting with 40% ethyl acetate/heptane. The productfractions were combined, concentrated under reduced pressure, driedunder high vacuum to a glass, and converted as previously described toadditional product (3.5 g, 7.2 mmol, 12%, total yield 73%). ¹H NMR (400MHz, DMSO-d₆) δ 11.50 (1H), 8.87-8.88 (1H), 8.29-8.32 (1H), 8.12-8.14(1H), 7.93-7.94 (2H), 7.39-7.46 (2H), 7.30-7.37 (3H), 5.32 (2H),5.21-5.25 (1H), 2.06-2.19 (2H), 1.26-1.63 (8H), 1.01-1.06 (1H); m/z487.5 (M+H)⁺.

Example 48(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinicacid

Formula (1A-4) wherein R⁴ is

The compound of Example 47 (4.07 g, 8.35 mmol) was added to a 500 mLParr bottle, followed by ethyl acetate (50 mL) and ethanol (100 mL). Themixture was warmed until all of the solid dissolved, and then cooled toroom temperature. 10% Pd/C (450 mg) was added, and the mixture wasshaken under 50 psi hydrogen for 90 minutes. The reaction was filteredthrough a microfiber filter. The filtrate was concentrated under reducedpressure and dried under high vacuum at 50° C. to afford product as aglassy solid (3.0 g, 7.75 mmol, 90.6%). The glassy solid was stirredovernight in diethyl ether. The white solid precipitate was filtered,washed with diethyl ether, suction dried, and dried under high vacuum at50° C. to afford the title compound as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 13.10-13.25 (1H), 11.44 (1H), 8.83 (1H), 8.23-8.26 (1H),8.09-8.12 (1H), 7.94-7.95 (2H), 5.22-5.26 (1H), 2.06-2.17 (2H),1.29-1.64 (8H), 1.04-1.07 (1H); m/z 397.3 (M+H)⁺.

Example 49(S)-3-cyclopentyl-N-(2-ethyl-2H-[1,2,3]triazol-4-yl)-2-(4-trifluoromethyl-1H-imidazol-1-yl)propanamide

Formula (1A-4) wherein R⁴ is

Example 49 was synthesized in an analogous manner to that of Example 43from Intermediate I-8a and 2-ethyl-2H-1,2,3-triazol-4-amine (ChembridgeCorporation, San Diego, Calif.). ¹H NMR (400 MHz, CDCl₃) δ 8.19 (1H),7.93 (1H), 7.67 (1H), 7.49 (1H), 4.74 (1H), 4.34 (2H), 2.04-2.34 (2H),1.67-1.84 (2H), 1.57-1.63 (4H), 1.43-1.54 (4H), 1.07-1.22 (2H); m/z371.2 (M+H+).

Example 50(S)-3-cyclopentyl-N-(5-((S)-1,2-dihydroxyethyl)pyrazin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-4) wherein R⁴ is

To a solution of Intermediate (I-14a) (75 mg, 0.16 mmol) in THF (2.5 mL)was added 1N HCl (2.4 mL) and this was stirred at room temperature for18 h. After 1 day, the reaction was extracted with ethyl acetate twice.The combined organics were washed with aqueous saturated NaHCO₃ anddried over MgSO₄. Purification by silica gel chromatography (12g-SnapBiotage, heptane/ethyl acetate) afforded 30 mg of Example 50 as an oil.¹H NMR (400 MHz, CD₃OD) δ 9.28 (1H), 8.50 (1H), 7.94 (1H), 7.82 (1H),5.16 (1H), 4.83 (2H), 4.77 (1H), 3.77-3.94 (1H), 3.66-3.77 (1H),2.10-2.34 (2H), 1.40-1.89 (7H), 1.22-1.36 (2H); m/z 414.1 (M+H⁺).

Example 51(S)-3-cyclopentyl-N-[5-(methylsulfonyl)pyridin-2-yl]-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propanamide

Formula (1A-4) wherein R⁴ is

Intermediate (I-19a) (80 mg, 0.29 mmol),2-bromo-5-(methylsulfonyl)pyridine (69 mg, 0.29 mmol), cesium carbonate(144 mg, 0 44 mmol), Xantphos (26.2 mg, 0.04 mmol),tris(dibenzylideneacetone) palladium (14 mg, 0.015 mmol) were combinedin anhydrous degassed toluene (4 mL). The mixture was stirred at 100° C.for 12 hrs. The reaction was diluted with ethyl acetate (50 mL) andwashed with H₂O (10 mL), NaHCO₃ (aq, saturated, 10 mL), and brine (10mL), and dried (Na₂SO₄), filtered and concentrated. The crude productwas purified by chromatography (silica gel, 0 to100% EtOAc gradient inheptane) to give a gummy residue, which was precipitated using(Et₂O/Heptane/Dichloromethane) to afford the title compound as whitesolid (55 mg, 44%). ¹H NMR (400 MHz, CDCl₃) δ 8.80 (1H), 8.45 (1H), 8.35(1H), 8.22 (1H), 7.70 (1H), 7.50 (1H), 4.80 (1H), 2.16-2.25 (2H),1.68-1.86 (2H), 1.60-1.67 (2H), 1.45-1.56 (3H), 1.08-1.28 (5H); m/z430.9 (M+H)⁺.

Example 526-[(S)-3-cyclopentyl-2-(4-trifluoromethyl-1H-imidazol-1-yl)-propionylamino]-nicotinamide

Formula (1A-4) wherein R⁴ is

Intermediate (I-21a) (157 mg, 0.378 mmol) was taken up in THF (1.2 mL)and cooled in an ice water bath. To this was added NH₄OH (0.8 mL) andthis was allowed to slowly warm to room temperature overnight. Thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was extracted with a second portion of ethyl acetate andthe combined organics were washed with brine, dried over MgSO₄,filtered, and evaporated to give crude material. This material waspurified by flash chromatography (SiO₂, dichloromethane/methanol, 4 to10%) to afford 67.7 mg (45.3%) of Example 52 as a tan solid. ¹H NMR (400MHz, CDCl₃) δ 8.70-8.73 (1H), 8.09-8.19 (2H), 7.68 (1H), 7.53 (1H), 4.96(1H), 3.30-3.33 (1H), 2.98 (2H), 2.01-2.17 (1H), 1.69 (1H), 1.40-1.62(4H), 1.02-1.26 (4H); m/z 396.0 (M+H+).

Example 53 (S)-benzyl5-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyrazine-2-carboxylate

Formula (1A-4) wherein R⁴ is

Intermediate (I-8b) (157.5 mg, 0.57 mmol) was dissolved in drydichloromethane (6 mL) and stirred at room temperature under nitrogen.One drop of DMF was added, followed by oxalyl chloride (0.10 mL, 1.18mmol). After bubbling had subsided, the mixture was left stirring for 90minutes and then evaporated. The residue was dissolved in two successiveportions of 1,2-dichloroethane and evaporated to remove excess oxalylchloride, and the residue was dissolved in dry dichloromethane (4 mL).Intermediate (I-22a) (161 mg, 0.70 mmol) and pyridine (0.10 mL, 1.24mmol) were dissolved in dry dichloromethane (5 mL) and added to thesolution of acid chloride. The reaction was stirred at room temperatureunder nitrogen for 2 days. The reaction was then diluted withdichloromethane and water, and the organic layer was separated, washedwith brine, dried over sodium sulfate, filtered, and evaporated. Theresidue was purified by silica gel chromatography on a 40 g pre-packedcolumn, using 25% ethyl acetate/heptane, linear gradient to 100% ethylacetate. The product fractions were combined, evaporated, and driedunder high vacuum to afford the title compound (145 mg, 0.3 mmol, 52%)as a yellow glass. ¹H NMR (400 MHz, CDCl₃) δ 9.57 (1H), 8.96-8.97 (1H),8.30-8.32 (1H), 7.69 (1H), 7.50 (1H), 7.39-7.47 (2H), 7.32-7.38 (3H),5.45 (2H), 4.80-4.85 (1H), 2.04-2.25 (2H), 1.49-1.81 (7H), 1.11-1.18(2H); m/z 487.9 (M+H)⁺.

Example 54(S)-5-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyrazine-2-carboxylicacid,

Formula (1A-4) wherein R⁴ is

The compound of Example 53 (145 mg, 0.3 mmol) was dissolved in ethanol(6 mL) and ethyl acetate (3 mL) in a 250 mL Parr bottle. 10% palladiumon carbon (20 mg) was added, and the reaction was shaken under 50 psihydrogen for 90 minutes. The mixture was filtered, evaporated, and driedunder high vacuum to afford the title compound (109.2 mg, 0.27 mmol,92%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.76 (1H), 9.33 (1H), 8.95 (1H), 7.97(2H), 5.25-5.29 (1H), 2.17-2.25 (1H), 2.05-2.15 (1H), 1.28-1.64 (8H),1.01-1.08 (1H); m/z 398.3 (M+H)⁺.

Example 55 (S)-ethyl2-(3-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)-1H-pyrazol-1-yl)acetate

Formula (1A-4) wherein R⁴ is

Intermediate (I-8b) (145 mg, 0.525 mmol) was dissolved in drydichloromethane (5 mL) and stirred at room temperature under nitrogen.One drop of DMF was added, followed by oxalyl chloride (0.095 mL, 1.1mmol). After bubbling had subsided, the mixture was left stirring for 90minutes and then evaporated. The residue was dissolved in two successiveportions of 1,2-dichloroethane and evaporated to remove excess oxalylchloride, and the residue was dissolved in dry dichloromethane (4 mL).Ethyl 2-(3-amino-1H-pyrazol-1-yl)acetate hydrochloride (OakwoodProducts, Inc., West Columbia, S.C.) (130 mg, 0.630 mmol) and pyridine(0.130 mL, 1.61 mmol) were dissolved in dry dichloromethane (5 mL) andadded to the solution of acid chloride. The reaction was stirred at roomtemperature under nitrogen for 1 day. The reaction was then diluted withdichloromethane and water, and the organic layer was separated, washedwith brine, dried over sodium sulfate, filtered, and evaporated. Theresidue was purified by silica gel chromatography on a 12 g pre-packedcolumn, using 50% ethyl acetate/heptane, linear gradient to 75% ethylacetate. The product fractions were combined, evaporated, and driedunder high vacuum to afford the title compound (153 mg, 68%) as a whiteglass. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (1H), 7.71 (1H), 7.50 (1H), 7.36(1H), 6.74 (1H), 4.70-4.75 (3H), 4.20-4.25 (2H), 2.06-2.20 (2H),1.43-1.77 (7H), 1.25-1.29 (3H), 1.07-1.15 (2H); m/z 428.0 (M+H)⁺.

Example 56(S)-3-cyclopentyl-N-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-4) wherein R⁴ is

Under a nitrogen atmosphere intermediate (I-27d) was dissolved inanhydrous toluene (4 mL). Trimethylaluminum (2.00 M in toluene, 0.488mL) was added dropwise. This mixture was stirred at room temperature for30 min before a solution of intermediate (I-8a) in 4 mL1,2-dichloroethane was added. The reaction was then stirred at 80° C.After 21 h, the reaction was quenched with saturated aqueous Rochelle'ssalt. This was extracted twice with dichloromethane. The combinedorganics were dried over MgSO₄ and concentrated to afford material thatwas most likely a mixture of the hydroxy product and silyl-protectedproduct. This material was then dissolved in anhydrous THF (10 mL) andtetrabutylammonium fluoride (1.00 M in THF, 3.77 mL) was added. This wasstirred at room temperature for two days before partitioning betweenethyl acetate and water. The aqueous layer was extracted with ethylacetate and the combined organics dried over MgSO₄. Purification bysilica gel chromatography (40 g ISCO, 20-100% EtOAc in heptane),followed by filtering through a course frit to remove any solids, andtriturating several times with dichloromethane/ether and then with etherafforded the title compound as a white solid (0.1563 g). ¹H NMR (400MHz, CDCl₃) δ 9.03 (1H), 7.80 (1H), 7.56 (1H), 7.33 (1H), 6.74 (1H),4.83 (1H), 3.99 (2H), 3.93 (1H), 2.20-2.30 (1H), 2.07-2.18 (1H),1.49-1.88 (7H), 1.09-1.21 (8H); m/z 413.9 (M+H)⁺.

Example 57(S)-2-(3-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)-1H-pyrazol-1-yl)aceticacid

Formula (1A-4) wherein R⁴ is

The compound of Example 55 (153 mg, 0.358 mmol) and lithium hydroxide(50.6 mg, 1.18 mmol) were stirred at room temperature inTHF/methanol/water (1:1:1, 3 mL) for 2 hours. The reaction wasconcentrated, and water and 1N HCl were added to achieve a pH ofapproximately 4. A thick precipitate settled. Ethyl acetate was added,and the organic layer was washed with brine and dried over sodiumsulfate. The mixture was filtered, evaporated, and dried under highvacuum to afford the title compound (31.5 mg, 22%). ¹H NMR (400 MHz,CD₃OD) δ 7.91 (1H), 7.78 (1H), 7.52 (1H), 6.56 (1H), 5.01-5.05 (1H),4.81 (2H), 2.13-2.17 (2H), 1.50-1.81 (7H), 1.21-1.28 (1H), 1.11-1.18(1H); m/z 398.0 (M−H)⁻.

Example 58(S)-diethyl(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)methylphosphonate

Formula (1A-4) wherein R⁴ is

To a solution of intermediate (I-8c) (0.27 g, 0.9 mmol) indichloromethane (10 mL) was added intermediate (I-26d) (0.223 g, 0.9mmol) and pyridine (0.22 g, 2.74 mmol) at room temperature. The mixturewas stirred for 12 hours at room temperature under nitrogen. TLC(petroleum ether/ethyl acetate=1:1) indicated the reaction was complete.The reaction mixture was concentrated in vacuo and the residue waspurified by chromatography on silica to afford the title compound (270mg, 58.7%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (1H),8.09 (1H), 8.03 (1H), 7.62 (1H), 7.58 (1H), 7.45 (1H), 4.73 (1H), 4.01(4H), 3.06 (2H), 2.08 (2H), 1.70 (2H), 1.58 (3H), 1.48 (2H), 1.20 (6H),1.10 (2H); m/z 503.3 (M+H)⁺.

Example 59 (S)-diethyl6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-ylphosphonate

Formula (1A-4) wherein R⁴ is

To a solution of intermediate (I-8c) (0.329 g, 1.12 mmol) indichloromethane (8 mL) was added intermediate (I-25a) (0.257 g, 1.12mmol) and pyridine (0.265 g, 3.36 mmol) at room temperature. The mixturewas stirred for 12 hours at room temperature under nitrogen. TLC(petroleum ether/ethyl acetate=0:1) indicated the reaction was complete.The reaction mixture was concentrated in vacuo, the residue was purifiedby chromatography on silica to afford the title compound (360 mg, 66.2%)as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.61 (1H), 8.39 (1H),8.15 (1H), 8.10 (1H), 7.63 (1H), 7.44 (1H), 4.71 (1H), 4.07 (4H), 2.10(2H), 1.70 (2H), 1.58 (2H), 1.48 (3H), 1.28 (6H), 1.10 (2H); m/z 489.5(M+H)⁺.

Example 60(S)-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)methylphosphonicacid

Formula (1A-4) wherein R⁴ is

To a solution of the compound of Example 58 (138 mg, 0.27 mmol) indichloromethane (2 mL) was added bromotrimethylsilane (2 mL) at roomtemperature. The mixture was stirred for 12 hours at room temperatureunder nitrogen. LCMS indicated the reaction was complete. The reactionmixture was quenched with methanol (2 mL), and the mixture wasconcentrated in vacuo, the residue was purified by prep-HPLC to affordthe title compound (54.3 mg, 47.4%) as a white solid. ¹H NMR (400 MHz,CD₃OD): δ 8.23 (1H), 8.00 (1H), 7.98 (1H), 7.81 (1H), 7.73 (1H), 5.12(1H), 3.06 (2H), 2.18 (2H), 1.75 (1H), 1.70 (1H), 1.61 (3H), 1.51 (2H),1.30 (1H), 1.18 (1H); m/z 445.5 (M−H)⁻.

Example 61(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridine-3-sulfonicacid

Formula (1A-4) wherein R⁴ is

To a solution of intermediate (I-8c) (0.40 g, 1.35 mmol) indichloromethane (10 mL) was added 6-aminopyridinesulfonic acid (0.236 g,1.35 mmol; Toronto Research Chemicals, North York, Ontario, Canada) andpyridine (0.32 mL, 4.1 mmol) at room temperature. The mixture wasrefluxed for 12 hours under nitrogen. LCMS indicated the startingmaterial was not consumed completely. The reaction mixture wasconcentrated in vacuo, the residue was purified by chromatography onsilica to afford the title compound (47.2 mg, 8.1%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 11.18 (1H), 8.50 (1H), 7.98 (4H), 7.03 (1H),5.22 (1H), 2.18 (2H), 1.60 (4H), 1.48 (3H), 1.31 (1H), 1.11 (1H);m/z431.4 (M−H)⁻.

Example 62(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-ylphosphonicacid

Formula (1A-4) wherein R⁴ is

To a solution of the compound of Example 59 (170 mg, 0.348 mmol) indichloromethane (2 mL) was added bromotrimethylsilane (2 mL) at roomtemperature, and the mixture was stirred for 12 hours at roomtemperature under nitrogen. LCMS indicated the reaction was complete.The reaction mixture was quenched with methanol (2 mL) and the mixturewas concentrated in vacuo. The residue was purified by prep-HPLC toafford the title compound (47.1 mg, 30.0%) as a white solid. ¹H NMR (400MHz, CD₃OD): δ 8.64 (1H) 8.15 (2H) 7.93 (1H) 7.81 (1H) 5.12 (1H) 2.18(2H) 1.80 (1H) 1.70 (4H) 1.55 (2H) 1.30 (1H) 1.25 (1H); m/z431.4 (M−H)⁻.

Example 636-((S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl(methyl)phosphinicacid

Formula (1A-4) wherein R⁴ is

To a solution of intermediate (I-29f) (300 mg, 0.655 mmol) indichloromethane (4 mL) was added bromotrimethylsilane (2 mL) at roomtemperature, and the mixture was stirred for 12 hours at roomtemperature under nitrogen. TLC (dichloromethane/methanol=10:1)indicated the reaction was complete. The reaction mixture wasconcentrated in vacuo, the residue was washed with water (5 mL), andextracted with dichloromethane (20 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and evaporated in vacuo. Theresidue was purified by chromatography on silica to afford the titlecompound (132.3 mg, 46.9%) as a white solid and as a mixture ofdiastereomers. ¹H NMR (400 MHz, CD₃OD): δ 8.70 (1H), 8.28 (1H), 8.16(1H), 8.00 (1H), 7.88 (1H), 5.21 (1H), 2.20 (2H), 1.84 (1H), 1.75 (1H),1.70 (6H), 1.60 (2H), 1.46 (1H), 1.28 (1H); m/z 431.4 (M+H)⁺.

Example 64(S)-2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)aceticacid

Formula (1A-4) wherein R⁴ is

A solution of intermediate (I-30g) (207 mg, 0.488 mmol) and lithiumiodide (649 mg, 4.88 mmol) in ethyl acetate (5 mL) was refluxed for 24hours. LCMS indicated the starting material was not consumed completely.The reaction mixture was concentrated in vacuo and the residue waspurified by prep-HPLC to afford the title compound (36.9 mg, 18.45%) asa white solid.

¹H NMR (400 MHz, CD₃OD): δ 8.14 (1H), 7.99 (1H), 7.85 (1H), 7.73 (1H),7.68 (1H), 5.10 (1H), 3.54 (2H), 2.11 (2H), 1.75 (1H), 1.63 (1H), 1.55(3H), 1.48 (2H), 1.21 (1H), 1.18 (1H); m/z 441.4 (M+H)⁺.

Example 65(S)-2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-yl)-2-methylpropanoicacid

Formula (1A-4) wherein R⁴ is

A solution of intermediate (I-31 e) (220 mg, 0.486 mmol) and LiI (647mg, 4.86 mmol) in EtOAc (11 mL) was refluxed for 72 hours. LCMSindicated the starting material was not consumed completely. Thereaction mixture was concentrated in vacuo, the residue was purified byprep-HPLC to afford Example 65 (45.6 mg, 21.3%) as a white solid. ¹H NMR(400 MHz, CD₃OD): δ 8.25 (1H), 7.94 (1H), 7.85 (1H), 7.73 (2H), 5.04(1H), 2.10 (2H), 1.73 (1H), 1.65 (1H), 1.55 (3H), 1.50 (6H), 1.48 (2H),1.23 (1H), 1.09 (1H); m/z 439.4 (M+H)⁺.

Example 66(S)-2-(6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)pyridin-3-ylamino)-2-oxoaceticacid

Formula (1A-4) wherein R⁴ is

A mixture of intermediate (I-32c) (280 mg, 0.599 mmol) and lithiumiodide (796 mg, 5.99 mmol) in ethyl acetate (14 mL) was refluxed for 24hours. LCMS indicated the reaction was complete. The reaction mixturewas concentrated in vacuo and the residue was purified by prep-HPLC toafford the title compound (119.1 mg, 45.3%) as a white solid. ¹H NMR(400 MHz, CD₃OD): δ 8.72 (1H), 8.16 (2H), 7.97 (1H), 7.85 (1H), 5.17(1H), 2.21 (2H), 1.84 (1H), 1.75 (1H), 1.70 (3H), 1.60 (2H), 1.32 (1H),1.18 (1H); m/z 440.2 (M+H)⁺.

Example 67(S)-3-Cyclopentyl-N-[5-(2-hydroxy-2-methyl-propionylamino)-pyridin-2-yl]-2-(4-trifluoromethyl-imidazol-1-yl)-propionamide

Formula (1A-4) wherein R⁴ is

To a solution of intermediate (I-33a) (350 mg, 0.70 mmol) in methanol(8.75 mL) and water (8.75 mL) was added potassium carbonate (146.4 mg,1.05 mmol) at room temperature, and the mixture was stirred for 12 hoursat room temperature. TLC (petroleum ether/ethyl acetate=1:1) indicatedthe reaction was complete. The reaction mixture was washed with aq.ammonium chloride (20 mL) and the mixture was extracted with ethylacetate (10 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and evaporated in vacuo. The residue was purified bychromatography on silica to afford the title compound (177.9 mg, 55.6%)as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.63 (1H), 8.10 (2H), 7.97(1H), 7.86 (1H), 5.14 (1H), 2.04 (2H), 1.85 (1H), 1.80 (1H), 1.70 (3H),1.58 (2H), 1.47 (6H), 1.35 (1H), 1.20 (1H); m/z 454.2 (M+H)⁺.

Examples 68-70 of Formula (1A-5) are provided below.

Example 68(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide

Formula (1A-5) wherein R⁴ is

To a stirred solution of of 1-methyl-3-aminopyrazole (1.219 g, 1.25mmol) in dichloroethane (2 mL) at 0° C. was added

Al(CH₃)₂Cl (1.0 M, 1.25 mL, 1.25 mmol) and stirred for 15 minutes. Asolution of Intermediate I-9a1 (50 mg, 0.16 mmol) in 0.5 mL of1,2-dichloroethane was then added and the reaction mixture was stirredat room temperature for 16 hours. The mixture was quenched with 20%potassium sodium tartrate tetrahydrate (5 mL) slowly and then dilutedwith water (30 mL) and extracted with CHCl₃ (30 mL). The organic layerwas dried over Na₂SO₄ and concentrated. The residue was purified onBiotage column (SiO₂, dichloromethane/methanol, 0 to 8%) to afford thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ 8.99 (1H), 7.64 (1H), 7.22(1H), 6.60 (2H), 4.99 (1H), 3.85 (3H), 2.22 (2H),1.73 (1H), 1.44-1.58(6H), 1.10-1.20 (1H), 1.02-1.07 (1H); m/z 356.2 (M+H)⁺.

Example 69(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide

Formula (1A-5) wherein R⁴ is

Example 69 was synthesized in an analogous manner to that of Example 68from Intermediate I-9a1 and 2-amino-5-methylpyridine. ¹H NMR (400 MHz,CDCl₃) δ 9.31 (1H), 8.94 (1H), 8.12 (1H), 7.63 (1H), 6.62 (1H),4.95-4.99 (1H), 2.50 (3H), 2.21-2.38 (2H), 1.68-1.81 (1H), 1.44-1.64(4H), 1.07-1.30 (4H); m/z 367.0 (M+H)⁺.

Example 70(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide

Formula (1A-5) wherein R⁴ is

Example 70 was synthesized in an analogous manner to that of Example 68from Intermediate I-9a1 and 2-amino-5-methylpyrazine. ¹H NMR (400 MHz,CDCl₃) δ 9.31 (1H), 8.94 (1H), 8.12 (1H), 7.63 (1H), 6.62 (1H),4.95-4.99 (1H), 2.50 (3H), 2.21-2.38 (2H), 1.68-1.81 (1H), 1.44-1.64(4H), 1.07-1.30 (4H); m/z 368.0 (M+H)⁺.

Examples 71-73 of Formula (1A-6) are provided below.

Example 71(S)-1-(3-cyclopentyl-1-(1-methyl-1H-pyrazol-3-ylamino)-1-oxopropan-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

Formula (1A-6) wherein R⁴ is

Example 71 was synthesized in an analogous manner to that of Example 68from Intermediate I-9a2 and 3-amino-1-methylpyrazole. ¹H NMR (400 MHz,CDCl₃) δ 9.46 (1H), 7.93 (1H), 7.82 (1H), 7.17 (1H), 6.55 (1H),4.87-4.91 (1H), 3.72 (3H), 3.15 (3H), 3.03 (3H), 2.19-2.49 (2H),1.38-1.68 (7H), (1H), 1.08-1.17 (1H), 0.97-1.02 (1H); m/z 359.2 (M+H)⁺.

Example 72(S)-1-(3-cyclopentyl-1-(5-methylpyridin-2-ylamino)-1-oxopropan-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

Formula (1A-6) wherein R⁴ is

Example 72 was synthesized in an analogous manner to that of Example 68from Intermediate I-9a2 and 2-amino-5-methylpyridine. ¹H NMR (400 MHz,CDCl₃) δ 12.61 (1H), 8.48 (1H), 8.17 (2H), 8.03 (1H), 7.79 (1H), 5.28(1H), 3.24 (3H), 3.08 (3H), 2.43 (3H), 2.16-2.32 (2H), 1.44-1.77 (6H),1.26 (2H), 1.08-1.14 (1H); m/z 370.1 (M+H)⁺.

Example 73(S)-1-(3-cyclopentyl-1-(5-methylpyrazin-2-ylamino)-1-oxopropan-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

Formula (1A-6) wherein R⁴ is

Example 73 was synthesized in an analogous manner to that of Example 68from Intermediate I-9a2 and 2-amino-5-methylpyrazine. ¹H NMR (400 MHz,CDCl₃) δ 9.61 (1H), 9.32 (1H), 8.08 (1H), 7.95 (1H), 7.88 (1H),4.94-4.98 (1H), 3.19 (3H), 3.07 (3H), 2.49 (3H), 2.29-2.37 (2H),1.40-1.76 (7H), 1.05-1.19 (2H); m/z 371.1 (M+H)⁺.

Examples 74-78 of Formula (1A-7) are provided below.

Example 74(S)—N-(5-methylpyrazin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-7) wherein R⁴ is

2-amino-5-methylpyrazine (Anichem LLC., Northbrunswick, N.J.) (48.2 mg,0.44 mM) was weighed into an 8 dram Arqule vial and stirred in anhydroustoluene (0.5 mL). Trimethylaluminum solution (0.23 mL, 2.0M in toluene)was added, and the reaction was sealed and stirred at room temperaturefor 45 minutes. A 1 mL aliquot of dichloroethane was added to 63 mg(0.21 mmol) of Intermediate I-10h, the reaction was sealed and stirredat 80° C. The reaction was cooled, and the residue was diluted withdichloromethane and 0.5 M Rochelle salt, shaken, and allowed to standfor 90 minutes. The mixture was filtered through an Autovial filter toremove insoluble material. The organic layer was filtered through anAlltech filter and dried under nitrogen. Chromatographic (column:Phenomenex Luna (2) C18, 150×4.6 mm, 5p. (21.2×150 mm 5μ), gradient 0.1%formic acid in water and 0.1% formic acid in acetonitrile (5 to 95%)purification of the crude product to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ 9.38 (1H), 9.05 (1H), 8.06 (1H), 7.70 (1H), 7.50(1H), 4.92 (1H), 3.89-3.94 (2H), 3.27-3.33 (2H), 2.53 (3H), 2.04-2.18(2H), 1.33-1.62 (5H); m/z 384.2 (M+H)⁺.

Example 75(S)—N-(5-methylpyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-7) wherein R⁴ is

Example 75 was synthesized in an analogous manner to that of Example 74from Intermediate I-10h and 2-amino-5-methylpyridine. ¹H NMR (400 MHz,CDCl₃) δ 9.62 (1H), 8.09-8.11 (1H), 8.02 (1H), 7.70 (1H), 7.58-7.60(1H), 7.51 (1H), 4.87-4.91 (1H), 3.89-3.95 (2H), 3.26-3.33 (2H), 2.31(3H), 2.02-2.17 (2H), 1.34-1.64 (5H); m/z 383.2 (M+H)⁺.

Example 76(S)—N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-7) wherein R⁴ is

Example 76 was synthesized in an analogous manner to that of Example 74from Intermediate I-10h and 3-amino-1-methylpyrazole. ¹H NMR (400 MHz,CD₃OD) δ 7.91 (1H), 7.78 (1H), 7.42 (1H), 6.47 (1H), 5.10-5.14 (1H),3.85-3.91 (2H), 3.78 (3H), 3.28-3.35 (2H), 2.07-2.10 (2H), 1.31-1.69(5H); m/z 372.2 (M+H)⁺.

Example 77(S)-3-(tetrahydro-2H-pyran-4-yl)-N-(thiazolo[5,4-b]pyridin-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-7) wherein R⁴ is

Example 77 was synthesized in an analogous manner to that of Example 74from Intermediate I-10h and thiazolo[5,4-b]pyridine-2-ylamine (AstaTech,Inc., Bristol, Pa.). ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.51 (1H), 7.89-7.91(1H), 7.71 (1H), 7.55 (1H), 7.35-7.38 (1H), 5.12-5.17 (1H), 3.91-3.94(2H), 3.28-3.53 (2H), 2.24-2.31 (1H), 2.06-2.11 (1H), 1.34-1.62 (5H);m/z 426.1 (M+H)⁺.

Example 78(S)—N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Formula (1A-7) wherein R⁴ is

Example 78 was synthesized in an analogous manner to that of Example 74from Intermediate I-10h and 5-methoxythiazolo[5,4-b]pyridin-2-amine(Maybridge, Tevillett, Cornwall, UK). ¹H NMR (400 MHz, CDCl₃) δ7.79-7.81 (1H), 7.78 (1H), 7.54 (1H), 6.79-6.81 (1H), 5.06-5.11 (1H),3.98 (3H), 3.91-3.97 (2H), 3.28-3.35 (2H), 2.21-2.28 (1H), 2.06-2.12(1H), 1.31-1.62 (5H); m/z 456.1 (M+H)⁺.

Examples 79-81 of Formula (1A-8) are provided below.

Example 79(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(5-(methylsulfonyl)-2H-tetrazol-2-yl)propanamide

Formula (1A-8) wherein R⁴ is

3-Amino1-methylpyrazole (38.9 mg, 0.40 mmol) was stirred in anhydroustoluene (2 mL). Trimethylaluminum solution (0.21 mL, 2.0M in toluene)was added, and the reaction was stirred at room temperature for 35minutes. A 2 mL aliquot of dichloroethane was added to 60 mg (0.20 mmol)of Intermediate I-11b. This solution was added and the stirred at 80° C.for 16 h. The reaction was cooled and stirred for several minutes withaqueous saturated Rochelle's salt. This was extracted twice withdichloromethane and the combined organics were dried over MgSO₄ andconcentrated under reduced pressure. Chromatographic purification of thecrude product afforded 13.5 mg of the title compound. ¹H NMR (400 MHz,CDCl₃) δ 8.67 (1H), 7.26 (1H), 6.60 (1H), 5.67 (1H), 3.80 (3H), 3.42(3H), 2.54-2.64 (1H), 2.38-2.48 (1H), 1.76-1.86 (1H), 1.55-1.76 (4H),1.44-1.54 (2H), 1.02-1.27 (2H); m/z 366.4 (M−H)⁻.

Example 80(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(5-(methylsulfonyl)-2H-tetrazol-2-yhpropanamide

Formula (1A-8) wherein R⁴

Example 80 was synthesized in an analogous manner to that of Example 79from Intermediate I-11b and 2-amino-5-methylpyridine. ¹H NMR (400 MHz,CDCl₃) δ 9.02 (1H), 8.17 (1H), 7.97 (1H), 6.96 (1H), 5.62-5.74 (1H),3.43 (3H), 2.58-2.71 (1H), 2.39-2.48 (1H), 2.37 (3H), 1.45-1.85 (7H),1.05-1.25 (2H); m/z 379.5 (M+H)⁺.

Example 81(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-(5-(methylsulfonyl)-2H-tetrazol-2-yhpropanamide

Formula (1A-8) wherein R⁴

Example 81 was synthesized in an analogous manner to that of Example 79from Intermediate I-11b and 2-amino-5-methylpyrazine. ¹H NMR (400 MHz,CDCl₃) δ 9.31 (1H), 8.43 (1H), 8.14 (1H), 5.75 (1H), 3.45 (3H),2.62-2.72 (1H), 2.55 (3H), 2.40-2.51 (1H), 1.46-1.90 (7H), 1.07-1.31(2H); m/z 378.4 (M−H)⁻.

Example 82(2S)—N-(5-methylpyridin-2-yl)-3-(tetrahydrofuran-2-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide,of Formula (1A-9)

To a solution of 5-methylpyridin-2-amine (205 mg, 1.9 mmol) in 4 mL ofdimethoxyethane was added dimethylaluminum chloride (1.0 M in hexanes,3.8 mL, 1.8 mmol). After the light yellow solution was stirred for 0.5hours, a solution of intermediate (I-12e) (185 mg, 0.63 mmol) in 2.3 mLof dimethoxyethane was added into the mixture. The reaction was heatedas a mixture at 90° C. overnight before cooling to room temperature. Thecrude reaction mixture was taken up in ethyl acetate and washed with0.5M aqueous Rochelle's salt. The aqueous layer was re-extracted withethyl acetate twice. The combined organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica gel chromatography (ISCO 12 g, 30-60%ethyl acetate/heptane) to afford the title compound as a yellow solidand as a mixture of diastereomers (85 mg, yield 36%). ¹H NMR (400 MHz,DMSO-d₆) δ 10.93 (1H), 8.16-8.20 (1H), 7.88-7.97 (3H), 7.59-7.65 (1H),5.29-5.40 (1H), 3.71-3.80 (1H), 3.44-3.66 (2H), 2.28-2.46 (1H), 2.25(3H), 2.12-2.22 (1H), 1.38-1.99 (6H); m/z 369.1 (M+H)⁺.

Example 83(S)—N-(5-methylpyridin-2-yl)-3-(1H-pyrazol-1-yl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propenamide,of Formula (1A-10)

5-Methylpyridin-2-amine (97 mg, 0.9 mmol) was weighed into an 8-dramArqule vial and stirred in dry toluene (1.0 mL). Trimethylaluminum (0.44mL, 2.0 M in toluene, 0.88 mmol) was added, and the reaction was sealedand stirred at room temperature for 45 minutes. Intermediate (I-13c)(116.3 mg, 0.40 mmol) in 1,2-dichloroethane (2.0 mL) was added, and thereaction was sealed and warmed to 80° C. for 16 hours. The reaction wascooled and shaken with 0.5M aqueous Rochelle salt solution (1 mL).Dichloromethane (1 mL) was added, and the mixture was stirred for 40minutes. The mixture was suction filtered, and the organic phase of thefiltrate was run through an Alltech filter and evaporated. The materialwas purified (Combi-flash, Redi-sep 40 g, 1:1 ethyl acetate/heptanegradient to 100% ethyl acetate), and the putative product fractions werecombined and evaporated. TLC (5% methanol/dichloromethane) showed thatthe residue contained two components. The material was purified bysilica prep TLC, developing with 6% methanol/dichloromethane. Threenarrow, close together bands were scraped off and crushed, and thecompounds were leached off with 1:1 ethyl acetate/methanol and filtered.The solvent was removed under a nitrogen stream. The residues werechecked by LC-MS to locate the desired product mass. The materialcontaining the product was purified by LC (Phenomenex Gemini C1821.2×150 mm, 5 um, modifier 0.1% ammonium hydroxide, 95% water/5%acetonitrile linear gradient to 5% water/95% acetonitrile) to afford thetitle compound (19.2 mg, 0.053 mmol, 13%). ¹H NMR (400 MHz, CDCl₃) δ8.06-8.08 (2H), 7.55-7.60 (2H), 7.42-7.45 (2H), 7.13-7.14 (1H),6.16-6.17 (1H), 5.47-5.51 (1H), 4.86-4.91 (1H), 4.54-4.59 (1H), 2.31(3H); m/z 365.0 (M+H)⁺.

Examples 84-89 represented of Formula (1A-11) are provided below.

Example 84(S)-3-cyclopentyl-N-(pyrazin-2-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamide

Formula (1A-11) wherein R⁴

is Trimethylaluminum (2 M in heptane, 0.510 mL, 1.02 mmol) was added toa solution of 2-aminopyrazine (97 mg, 1.02 mmol) in dry toluene (4 mL)under argon at 0° C., and the resulting reaction mixture warmed toambient temperature and stirred for 30 minutes. After this time, asolution of intermediate (I-15b) (99 mg, 0.34 mmol) in tetrahydrofuran(4 mL) was added dropwise to the reaction mixture and the reactionheated to reflux overnight. After cooling to ambient temperature, thereaction was quenched with the addition of ammonium chloride (aq.) (5mL), and the product extracted with ethyl acetate (2×10 mL), washed withbrine (10 mL), dried over MgSO₄, filtered and the solvent removed undervacuum. Purification was then achieved by flash chromatography (2:1hexane/ethyl acetate) to afford the title compound as a colorlessviscous oil (81 mg, 67% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.46 (1H),8.63 (1H), 8.41 (1H), 8.38 (1H), 8.29 (1H), 5.10 (1H), 2.39-2.27 (2H),1.66-1.79 (1H), 1.75-1.49 (6H), 1.27-1.10 (2H); m/z 354.9 (M+H)⁺.

Example 85(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamide

Formula (1A-11) wherein R⁴ is

Example 85 was synthesized in an analogous manner to that of Example 84from Intermediate I-15b and 2-amino-5-methylpyridine. ¹H NMR (400 MHz,CDCl₃) δ 8.54 (1H), 8.41 (1H), 8.13 (1H), 8.01 (1H), 7.53 (1H), 5.04(1H), 2.31-2.27 (2H), 2.30 (3H), 1.83-1.77 (1H), 1.75-1.58 (4H),1.54-1.47 (2H), 1.23-1.08 (2H); m/z 367.9 (M+H)⁺.

Example 86 (S)-benzyl6-(3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamido)nicotinate

Formula (1A-11) wherein R⁴ is

Intermediate (I-15c) (180 mg, 0.65 mmol) was stirred in drydichloromethane (5 mL) at room temperature under nitrogen. One drop ofdimethylformamide was added, followed by oxalyl chloride (0.12 mL, 1.3mmol). After bubbling had subsided, the reaction was left stirring for90 minutes and then evaporated. The residue was re-dissolved in1,2-dichloroethane and re-evaporated twice to remove unreacted oxalylchloride, and then the residue was dissolved in dry dichloromethane (5mL). Intermediate (I-28a) (180 mg, 0.789 mmol) and pyridine (0.11 mL,1.36 mmol) were added to the acid chloride solution, and the reactionwas stirred for 18 hours. The reaction was diluted with dichloromethaneand water. The organic layer was washed with brine, dried over sodiumsulfate, filtered, evaporated, and the residue was purified by silicagel chromatography, using a 12 g pre-packed column, eluting with 25%ethyl acetate/heptane. The product fractions were combined, evaporated,and dried under high vacuum to afford the title compound (262 mg, 0.537mmol, 83%) as a white glass. ¹H NMR (400 MHz, CDCl₃) δ 8.95 (1H), 8.82(1H), 8.39 (1H), 8.32-8.34 (1H), 8.17-8.19 (1H), 7.34-7.44 (5H), 5.36(2H), 5.08-5.11 (1H), 2.28-2.33 (2H), 1.49-1.81 (7H), 1.08-1.21 (2H);m/z 488.0 (M+H)⁺.

Example 87 (S)-ethyl2-(3-(3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamido)-1H-pyrazol-1-yl)acetate

Formula (1A-11) wherein R⁴ is

Intermediate (I-15c) (180 mg, 0.65 mmol) was stirred in drydichloromethane (5 mL) at room temperature under nitrogen. One drop ofdimethylformamide was added, followed by oxalyl chloride (0.12 mL, 1.3mmol). After bubbling subsided, the reaction was left stirring for 90minutes and then evaporated. The residue was re-dissolved in1,2-dichloroethane and re-evaporated twice to remove unreacted oxalylchloride, and then taken up in dry dichloromethane (5.0 mL). Ethyl2-(3-amino-1H-pyrazol-1-yl)acetate hydrochloride (Oakwood Products,Inc., West Columbia, S.C.) (160 mg, 0.78 mmol) and pyridine (0.16 mL,2.0 mmol) were added, and the reaction was stirred for 18 hours. Thereaction was diluted with dichloromethane and water, and the organiclayer was washed with brine, dried over sodium sulfate, and evaporated.The residue was purified by silica gel chromatography, using a 12 gpre-packed column, eluting with 25% ethyl acetate/heptane with a lineargradient to 50% ethyl acetate. The product fractions were combined,evaporated, and dried under high vacuum to afford the title compound(174 mg, 0.406 mmol, 62%) as a white glass. ¹H NMR (400 MHz, CDCl₃) δ8.48 (1H), 8.37 (1H), 7.36 (1H), 6.72 (1H), 4.99-5.03 (1H), 4.77 (2H),4.19-4.25 (2H), 2.20-2.30 (2H), 1.46-1.81 (7H), 1.25-1.29 (3H),1.04-1.22 (2H); m/z 429.0 (M+H)⁺.

Example 88(S)-6-(3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamido)nicotinicacid

Formula (1A-11) wherein R⁴ is

The compound of Example 86 (262 mg, 0.537 mmol) was dissolved in ethylacetate (4 mL) and ethanol (6 mL) in a small Parr bottle. 10% Palladiumon carbon (40 mg) was added, and the reaction was shaken under 50 psihydrogen for 2 hours. The mixture was filtered, evaporated, and driedunder high vacuum at 50° C. to afford the title compound (176.3 mg, 0.44mmol, 82%) as a white glass. ¹H NMR (400 MHz, CD₃OD) δ 8.88-8.90 (2H),8.29-8.32 (1H), 8.16-8.18 (1H), 5.42-5.47 (1H), 2.24-2.36 (2H),1.49-1.80 (7H), 1.28-1.33 (1H), 1.14-1.17 (1H); m/z 396.0 (M−H)⁻.

Example 89(S)-2-(3-(3-cyclopentyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamido)-1H-pyrazol-1-yl)aceticacid

Formula (1A-11) wherein R⁴ is

The compound of Example 87 (174 mg, 0.406 mmol) and lithium hydroxide(57.4 mg, 1.34 mmol) were stirred at room temperature in tetrahydrofuran(2 mL), methanol (2 mL) and water (2 mL) for 2 hours. The mixture wasconcentrated, and water and 1N HCl were added to reach approximately pH4. A dense solid crashed out. Ethyl acetate was added, and the organiclayer was washed with brine and dried over sodium sulfate. The mixturewas filtered, evaporated, and dried under high vacuum to afford thetitle compound (160 mg, 0.40 mmol, 99%) as a white glass. ¹H NMR (400MHz,CDCl₃) δ 10.21 (1H), 8.40 (1H), 7.35 (1H), 6.78 (1H), 5.03-5.07(1H), 4.75 (2H), 2.03-2.24 (2H), 1.41-1.75 (7H), 1.01-1.26 (2H); m/z399.0 (M−H)⁻.

Example 90(S)-6-(3-cyclohexyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinicacid, of Formula (1A-12)

Intermediate (I-16e) (0.145 mg, 290 mmol) was taken up in 30 mL ofmethanol and was injected onto an H-Cube™. Hydrogenation occurred undera continuous flow of H₂ on a 10% Pd/C cartridge at a flow rate of 1 mLper min. The filtrate was collected and concentrated to afford the titlecompound. ¹H NMR (400 MHz, CD₃OD) δ 8.90-8.89 (1H), 8.32-8.29 (1H),8.20-8.17 (1H), 7.93 (1H), 7.81 (1H), 5.28-5.24 (1H), 2.08-2.04 (2H),1.84-1.81 (1H), 1.73-1.63 (4H), 1.18-1.16 (3H), 1.07-0.99 (3H); m/z 411(M+H)⁺.

Examples 91-92 of Formula (1A-13) are provided below.

Example 91(S)-3-cyclopentyl-2-(2-methyl-4-(trifluoromethyl)-1H-imidazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide

Formula (1A-13) wherein R⁴ is

5-methylpyridin-2-amine (96 mg, 0.88 mmol) was taken up in 4 mL ofdimethoxyethane and cooled to 0° C. Dimethyaluminium chloride (1.48mmol, 1M in hexane) was added dropwise. The resulting mixture was warmedup to ambient temperature and stirred for 30 min. A solution ofintermediate (I-17a) (90 mg, 0.3 mmol) in dimethoxyethane (2 mL) wasthen added to the activated amine solution via canula. The combinedsolution was heated to reflux overnight. The reaction was cooled to roomtemperature and slowly quenched by the dropwise addition of aqueousRochelle's salt (concentrated, 10 mL). The mixture was stirred for 20minutes before separating the layers. The organic layer was washed withaqueous Rochelle's salt (10 mL) and then brine (30 mL), dried overmagnesium sulfate, and concentrated in vacuo. The crude product waspurified by column chromatography (silica gel, gradient of ethyl acetatefrom 20-100% in heptane) to afford the title compound in 11% yield. ¹HNMR (400 MHz, CDCl₃) δ 8.19 (1H), 7.96-8.10 (2H), 7.53 (1H), 7.46 (1H),4.64 (1H), 2.42 (3H), 2.25-2.32 (3H), 2.14-2.25 (1H), 2.00-2.13 (1H),1.43-1.78 (7H), 1.04-1.30 (2H); m/z 381.4 (M+H)⁺.

Example 92(S)-6-(3-cyclopentyl-2-(2-methyl-4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinicacid

Formula (1A-13) wherein R⁴ is

Intermediate (I-17b) was dissolved in methanol (2 mL) and thenhydrogenated with an H-Cube™ at full H₂ and 1 mL/min on a Pd-Ccartridge. TLC (10% methanol/dichloromethane) showed most of thestarting material had reacted. The reaction solution was concentratedand the crude material was purified by silica gel chromatography (4 gcolumn, 0-15% methanol in dichloromethane) to afford the title compound.¹H NMR (400 MHz, CDCl₃) δ 11.73 (1H), 9.01 (1H), 8.54 (2H), 7.58 (1H),5.04 (1H), 2.54 (3H), 2.17-2.31 (1H), 2.03-2.17 (1H), 1.76-1.91 (2H),1.45-1.74 (6H), 1.27-1.44 (1H), 1.07-1.24 (1H); m/z 411.4 (M+H)⁺.

Examples 93-95 of Formula (1A-14) are provided below.

Example 93(S)-3-cyclopentyl-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide

Formula (1A-14) wherein R⁴ is

5-methylpyridin-2-amine (144 mg, 1.33 mmol) was taken up in 4 mL ofdimethoxyethane and cooled to 0° C. Dimethyaluminium chloride (2.22mmol, 1M in hexane) was added dropwise. The resulting mixture was warmedup to ambient temperature and stirred for 30 min. A solution ofintermediate (I-18a) (135 mg, 0.44 mmol) in dimethoxyethane (2 mL) wasthen added to the activated amine solution via canula. The combinedsolution was heated to reflux overnight. The reaction was cooled to roomtemperature and slowly quenched by the dropwise addition of aqueousRochelle's salt (concentrated, 10 mL). The mixture was stirred for 20minutes before separating the layers. The organic layer was washed withaqueous Rochelle's salt (10 mL), and then brine (30 mL), dried overmagnesium sulfate, and concentrated in vacuo. The crude product waspurified by column chromatography (silica gel, gradient of ethyl acetatefrom 20-100% in heptane) to afford the title compound in 41% yield. ¹HNMR (400 MHz, CDCl₃) δ 8.56 (1H), 8.06-8.11 (1H), 7.99 (1H), 7.45-7.50(1H), 7.39 (1H), 4.84 (1H), 3.66-3.74 (1H), 2.16-2.33 (5H), 2.13-2.16(3H), 1.42-1.84 (6H), 1.01-1.21 (2H); m/z 381.4 (M+H)⁺.

Example 94 (S)-benzyl6-(3-cyclopentyl-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamido)nicotinate

Formula (1A-14) wherein R⁴ is

Intermediate (I-18b) (65 mg, 0.22 mmol) was stirred in drydichloromethane (5 mL) at room temperature under nitrogen. One drop ofdimethylformamide was added, followed by oxalyl chloride (0.04 mL, 0.46mmol). After bubbling subsided, the reaction was stirred for 90 minutesand then evaporated. The residue was re-dissolved in 1,2-dichloroethaneand re-evaporated twice to remove unreacted oxalyl chloride, and thenthe residue was taken up in dry dichloromethane (2.5 mL). Intermediate(I-28a) (61.4 mg, 0.269 mmol) and pyridine (0.048 mL, 0.48 mmol) wereadded, and the reaction was left to stir for 18 hours. The solvent wasevaporated and the residue was purified by silica gel chromatography,using a pre-packed 12 g column, eluting with 10% ethyl acetate/heptanewith a linear gradient to 50% ethyl acetate. The product fractions werecombined, evaporated, and dried under high vacuum to afford the titlecompound (68.4 mg, 0.14 mmol, 62%) as a white glass. ¹H NMR (400 MHz,CDCl₃) δ 9.10 (1H), 8.93 (1H), 8.28-8.31 (1H), 8.18-8.20 (1H), 7.33-7.43(6H), 5.33 (2H), 4.87-4.91 (1H), 2.16-2.35 (5H), 1.46-1.79 (7H),1.05-1.20 (2H); m/z 500.9 (M+H)⁺.

Example 95(S)-6-(3-cyclopentyl-2-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamido)nicotinicacid

Formula (1A-14) wherein R⁴ is

The compound of Example 94 (68 mg, 0.14 mmol) was dissolved in ethylacetate (2 mL) and ethanol (4 mL) in a small Parr bottle. 10% Palladiumon carbon (20 mg) was added, and the reaction was shaken under 30 psihydrogen for 90 minutes. The mixture was filtered, evaporated, and driedunder high vacuum to afford the title compound (47 mg, 0.11 mmol, 82%)as a clear glass. ¹H NMR (400 MHz, CD₃OD) δ 8.88 (1H), 8.28-8.30 (1H),8.16-8.18 (1H), 7.77 (1H), 5.19-5.23 (1H), 2.15-2.29 (5H), 1.45-1.83(7H), 1.08-1.30 (2H); m/z 410.9 (M+H)⁺.

Example 96(S)-3-cyclopentyl-2-(3-methyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-methylpyridin-2-yl)propanamide,of Formula (1A-15)

To a solution of 5-methylpyridin-2-amine (63.6 mg, 0.59 mmol) in 1.4 mLof dimethoxyethane was added dimethylaluminum chloride (1.0M in hexanes,1.2 mL, 1.2 mmol). After stirring for 1 hour at 0° C., it was pouredinto a solution of intermediates (I-20b) and (I-20c) (89.4 mg, 0.29mmol, combined) in 1.5 mL of dimethoxyethane. The mixture was heated atreflux for 3 h before cooling and concentrating. The residue was takenup in dichloromethane and stirred with saturated aqueous Rochelle'ssalts for 1 hour. The layers were separated and the aqueous layer wasreextracted with dichloromethane twice. The combined organic layer wasdried over sodium sulfate, filtered and concentrated. The crude materialwas purified by silica gel chromatography (ISCO 12 g, 30-60% ethylacetate/heptane) to afford Example 96 and Example 97. ¹H

NMR (400 MHz, CDCl₃) δ 9.18 (1H), 8.10-8.14 (1H), 8.02 (1H), 7.73 (1H),7.49 (1H), 4.73-4.82 (1H), 2.40 (3H), 2.27 (3H), 2.24-2.27 (1H),2.13-2.22 (1H), 1.37-1.81 (5H), 1.01-1.29 (4H); m/z 381.0 (M+H)⁺.

Example 97(S)-3-cyclopentyl-2-(5-methyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(5-methylpyridin-2-yl)propanamideof Formula (1A-16)

Prepared by the reaction described above for Example 96 to provide thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ 9.24 (1H), 8.08 (1H), 8.01(1H), 7.84 (1H), 7.48 (1H), 4.80 (1H), 2.42-2.51 (1H), 2.41 (3H), 2.26(3H), 2.14-2.24 (1H), 1.42-1.76 (5H), 0.97-1.32 (4H); m/z 380.9 (M+H)⁺.

Biological Assay

Full-length glucokinase (beta cell isoform) was His-tagged at N-terminusand purified by a Ni column followed by size exclusion chromatography. A320 mL column was packed in house using Superdex75 (Amersham Pharmacia,Carlsbad, Calif.) preparation grade resin. Glucose was obtained fromCalbiochem (San Diego, Calif.) and other reagents were purchased fromSigma-Aldrich (St. Louis, Mo.).

All assays were performed in a Corning 384-well plate using SpectramaxPLUS spectrophotometer (Molecular Devices, Sunnyvale, Calif.) at roomtemperature. The final assay volume was 40 ∥L. The buffer conditionsused in this assay were as follows: 50 mM HEPES, 5 mM glucose, 2.5 mMATP, 3.5 mM MgCl₂, 0.7 mM NADH, 2 mM dithiothreitol, 1 unit/mL pyruvatekinase/lactate dehydrogenase (PK/LDH), 0.2 mM phosphoenolpyruvate, and25 mM KCl. The buffer pH was 7.1. The test compound in dimethylsulfoxidesolution was added to the buffer and mixed by a plate shaker for 7.5minutes. The final concentration of dimethylsulfoxide introduced intothe assay was 0.25%.

Glucokinase was added to the buffer mixture to initiate the reaction inthe presence and absence of compound. The reaction was monitored byabsorbance at 340 nm due to the depletion of NADH. The initial reactionvelocity was measured by the slope of a linear time course of 0-300seconds. The percentage of maximum activation was calculated by thefollowing equation:

% Maximum Activation=(Va/Vo−1)×100;

wherein each of Va and Vo is defined as the initial reaction velocity inthe presence and absence of the tested compound, respectively.

To determine the EC₅₀ (half maximal effective concentration) and %maximum activation, compounds were serially diluted in dimethylsulfoxideby 3-fold. The glucokinase activities were measured as a function ofcompound concentrations. The data were fitted to the equation below toobtain the EC₅₀ and % max activation values:

Va/Vo=1+(% max activation/100)/(1+EC₅₀/compound concentration)

Beta Cell Glucokinase His-Tag Purification Growth and InductionConditions:

BL21(DE3) cells (Invitrogen Corporation, Carlsbad, Calif.) containingpBCGK (C or N His) vector were grown at 37° C. (in 2× YT) until theOD600 was between 0.6-1.0. Expression was induced by addition ofisopropylthiogalactoside to a final concentration of 0.1-0.2 mM to thecells which were then incubated overnight at 23° C. The next day, cellswere harvested via centrifugation at 5000 rpm for 15 minutes at 4° C.The cell pellet was stored at −80° C. for future purification.

Purification:

A Ni-NTA (Quigan, Germantown, Md.) column (15-50 mL) was used forseparation. Two buffers were prepared, 1) a lysis/nickel equilibrationand wash buffer and 2) a nickel elution buffer. Thelysis/equilibration/wash buffer was prepared as such: 25 mM HEPES bufferat pH 7.5, 250 mM NaCl, 20 mM imidazole, and 14 mM β-mercaptoethanol asfinal concentrations. The elution buffer was prepared as such: 25 mMHEPES at pH 7.5, 250 mM NaCl, 400 mM imidazole, and 14 mMβ-mercaptoethanol as final concentrations. The buffers were eachfiltered with a 0.22 μm filter prior to use. The cell pellet (1 Lculture) was resuspended in 300 mL of the lysis/equilibration buffer.The cells were then lysed (3 times) with a Microfluidics Model 110Ymicrofluidizer (Microfluidics Corporation, Newton, Mass.). The slurrywas centrifuged with a Beckman Coulter Model LE-80K ultracentrifuge(Beckman Coulter, Fullerton, Calif.) at 40,000 rpm for 45 minutes at 4°C. The supernatant was transferred to a chilled flask. A volume of 20 μlwas saved for gel analysis. A Pharmacia AKTA (GMI, Inc., Ramsey, Minn.)purification system was used for separation. The prime lines were purgedwith lysis/equilibration buffer. The Ni-NTA column was equilibrated with200 mL of the lysis/equilibration buffer at a flow rate of 5 mL/minute.The supernantant was loaded over the column at 4 mL/minute and theflow-through was collected in a flask. The unbound proteins were washedwith lysis/equilibration buffer at a flow rate of 5 mL/minute until theultraviolet reaches baseline. The protein was then eluted from thecolumn with the imidazole elution buffer via imidazole gradient 20 mM to400 mM over 320 mL. The column was then stripped of any additionalprotein with 80 mL of the elution buffer. The elution fractions wereeach 8 mL, for a total yield of 50 samples. Fractions were analyzed bysodium dodecyl sulfate polyacrylamide (SDS-PAGE) and the fractionscontaining protein of interest were pooled and concentrated to 10 mLusing ultrafiltration cell with a 10,000 molecular weight cut-off (MWCO)Millipore membrane (Sigma-Aldrich, St. Louis, Mo.) under nitrogen gas(60 psi). Protein was further purified by size exclusion chromatography(SEC) using a Sedex 75 evaporative light scattering detector (320 mL)(Amersham Pharmacia, Uppsala, Sweden). SEC was equilibrated with 450 mLsizing buffer containing 25 mM HEPES pH 7.0, 50 mM NaCl, and 5 mMdithiothreitol. Concentrated protein was then loaded over SEC andelution with 400 mL sizing buffer was performed overnight at 0.5mL/minute. The elution fractions were 5 mL each. The fractions wereanalyzed by SDS-PAGE and protein containing fractions were pooled.Concentration was measured using Bradford Assay/BSA Standard. Purifiedprotein was stored in small aliquots at −80° C.

Biological Data

The EC₅₀ (μM) and percent maximum activation data for Examples 1-97obtained from the biological procedures as defined above are presentedin the table below as a single value or range where the sample size (N)is >1.

Biological Data Table: EC₅₀ and Maximum Activation Percent as Determinedby the Methods described above.

EC₅₀ Maximum Example (μM) Activation (%) N 1 0.3-0.6 38-50 2 2  9.0-16.584-90 4 3 0.7-1.9 15-23 3 4 0.9-2.2 57-90 4 5 >100 na 2 6 4.8-5.6 70-762 7 3.5-6.0 39-40 2 8 3.8 100 1 9 55 174 1 10 4.8 56 1 11 32 110 112 >100 na 1 13 32 100 1 14 11 122 1 15 60 89 1 16 1.9 48 1 17 8.2 23 118 15.7 24 1 19 1.3-1.7 33-39 2 20 7.2 80 1 21 2.9 65 1 22 25 144 1 247.0 145 1 25 3.9 116 1 26 33 89 1 27 22 120 1 28 >100 na 1 29 17 112 130 10 100 1 31 11 125 1 33 16 136 1 34 62 236 1 35 0.8 100 1 36 23 125 138 2.3 160 1 43 2.9-3.5 147-166 2 44 1.1 111 1 45 2 161 1 48 0.2-0.7144-223 6 49 2.2 168 1 50 2.6-4.2 121-140 2 51 6.7-8.8  90-113 2 52 0.4110 1 54 28 123 1 56 5.2 167 1 57 8.2 138 1 58 3.4 129 1 59 14 81 1 604.6 112 1 61 5.1 123 1 62 >50 na 1 64 4.2 163 1 65 17 84 1 66 1.6 131 167 2.8 104 1 68 >100 na 1 69 5.5 90 1 70 24 124 1 71 >30 na 1 72 >100 na1 73 >100 na 1 74 8.7 115 1 75 0.8-2.0 51-78 4 76 18 138 1 77 18 139 178 4.2-4.4 109-114 2 79 40 99 1 80 32 86 1 81 >50 na 1 82 5.0 115 183 >100 na 1 84 10 171 1 85 0.8-1.0 125-147 2 88 0.7 150 1 89 45 183 190 0.2-0.3 120-138 2 91 0.4 120 1 92 0.4-1.2 158-168 2 93 4.0-5.4 92-952 95 8.0 128 1 96 2.8 123 1 97 28 136 1

1.(S)-6-(2-(4-(cyclobutylsulfonyl)-1H-imidazol-1-yl)-3-cyclopentylpropanamido)nicotinicacid or a pharmaceutically acceptable salt thereof.
 2. A compound ofstructure


3. A pharmaceutical composition comprising a therapeutically effectiveamount of the compound according to claim 1 and a pharmaceuticallyacceptable excipient, diluent, or carrier.